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Functions of p38 MAP Kinases in the Central Nervous System

Prita R. Asih, Emmanuel Prikas, Kristie Stefanoska and 3 more

Frontiers in Molecular Neuroscience · 2020 · Review · CC BY

doi:10.3389/fnmol.2020.570586

Abstract

Mitogen-activated protein (MAP) kinases are a central component in signaling networks in a multitude of mammalian cell types. This review covers recent advances on specific functions of p38 MAP kinases in cells of the central nervous system. Unique and specific functions of the four mammalian p38 kinases are found in all major cell types in the brain. Mechanisms of p38 activation and downstream phosphorylation substrates in these different contexts are outlined and how they contribute to functions of p38 in physiological and under disease conditions. Results in different model organisms demonstrated that p38 kinases are involved in cognitive functions, including functions related to anxiety, addiction behavior, neurotoxicity, neurodegeneration, and decision making. Finally, the role of p38 kinases in psychiatric and neurological conditions and the current progress on therapeutic inhibitors targeting p38 kinases are covered and implicate p38 kinases in a multitude of CNS-related physiological and disease states.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 23, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Extracellular and environmental stimuli need to be integrated for adequate cellular and organismal responses. Signal transduction is a key mechanism to translate stimuli into intracellular responses that converge in alterations in gene expression, of cellular shape and motility, and of metabolic activity. Mitogen-activated protein (MAP) kinases are central to multiple signal transduction pathways across a variety of cell types, including cells of the central and peripheral nervous systems, and are evolutionarily conserved across phyla. Among the three canonical MAP kinase classes are extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNK), and p38 MAP kinases. This review will focus on the functions of p38 MAP kinases in cells of the nervous system.

The p38 MAP Kinase Gene Family

p38 MAP kinases are encoded in four separate genes in mammalian genomes: p38α by the MAPK14 gene, p38β (MAPK11), p38γ (MAPK12), and p38δ (MAPK13) (Figure 1A). The structure of p38 kinases consists of N- and C-lobes of the kinase domain with the active site in between ATP binding site and TGY dual phosphorylation site. The active site is covered by the activation loop, which undergoes dual phosphorylation resulting in conformation change, permitting access of substrates to the active site and full kinase activation (Figure 1B).

Mammalian p38 genes arose from a common ancestor related to the single, orthologous HOG1 gene in yeast, and p38-encoding genes occur in organisms of different taxa in increasing number (Table 1). The four mammalian p38 genes emerged from tandem and segmental gene duplications, and genes MAPK14–MAPK11 and MAPK12–MAPK13, are co-located on chromosomes 22 and 6, respectively. Mammalian p38 proteins exhibit a high degree of similarity with 60 percent sequence identity between the four kinases and are expressed as one single gene product per gene, with the exception of p38α.

Expression of p38 MAP Kinases

Expression of p38α in different tissues is ubiquitous compared with that of p38β, p38γ, or p38δ. The four p38 isoforms were detected in whole mouse brain and cerebellum, while mainly p38α and p38β localize to cells in the murine neocortex and hippocampus, with lower levels of p38γ or p38δ. p38α and p38β are found in most cell types of the central nervous system, including in neurons, astrocytes, microglia, endothelial cells, and spinal cord. p38γ is expressed at relatively higher levels in muscle and liver, yet is found in most tissues. p38γ expression in brain is lower compared with other organs and it is found mainly in large pyramidal neurons of the cortex and hippocampus (A Ittner, unpublished results). Expression of p38δ is more restricted compared with other p38 kinases and is found in exocrine and endocrine pancreas, brain, lung, heart, and myeloid granulocytes. Thus, all four p38 kinases are present in the CNS, however, they serve non-redundant functions depending on cell type and context.

p38 MAP Kinase Signaling

p38 MAP kinases are engaged by a multitude of stimuli in a context- and cell type-dependent manner (Figure 1C). p38 was originally discovered as protein kinase activated in response to lipopolysaccharide (LPS) and osmotic stress and in regulation of cytokine biosynthesis. Work over the last 25 years established that p38 regulates various cellular functions such as metabolism, secretion, migration, differentiation, apoptosis, and senescence. p38 is activated by cellular stressors such as inflammatory cytokines (e.g., IL-1 and TNF-α), UV irradiation, osmotic pressure, and oxidative stress. Upstream stimuli engage a three-tiered hierarchical phosphorylation cascade to activate p38, involving sequential activation of a MAP kinase kinase kinase (MAP3K), a MAP2K, and finally the p38 MAP kinase. The p38-specific MAP2Ks MKK3 and MKK6 are dual-specificity kinases that phosphorylate Threonine (T) and Tyrosine (Y) residues within the Thr-Gly-Tyr motif of the activation loop of p38. Dual phosphorylation results in structural changes within the kinase domain and increased activity of p38. Scaffolding proteins (e.g., JIP4) recruit upstream MAP2Ks and MAP3Ks to potentiate activation of p38 kinases. Alternative modes of activation have been described, which are mediated by protein interaction, small molecules, and both tyrosine- and autophosphorylation of p38. Downstream targets of p38 include cytoskeletal and scaffold proteins, transcription factors, molecular chaperones, metabolic enzymes, and signaling factors. p38 is regulated by localization, e.g., between the cytoplasm and nuclear compartment and inactivated by transcriptional feedback, termination of stimuli, inhibition of upstream kinases or direct dephosphorylation by MAP kinase dual-specificity phosphatases (DUSPs). DUSPs specifically dephosphorylate threonine and tyrosine residues within the MAPK activation loop, including in p38, thus negatively regulating their activation. Several DUSPs have been found to target p38, including DUSP12, which regulates macrophage responses, DUSP1, DUSP8, DUSP10, and DUSP16, which are specific for p38 and JNK.

Small Molecule Inhibitors

Development of new kinase inhibitors is critical to studying protein kinase function. Small molecule inhibitors are key tools to study p38 function in many cell types including within the CNS (Table 2). The 1st generation of p38 inhibitors are based on imidazole-pyrimidine scaffolds and include SB239063, SB202190, and SB203580, which all target p38α and p38β at concentrations used in most experimental conditions, yet show no activity toward p38γ or p38δ. Additionally, specificity limitations of 1st generation p38 inhibitors led to off-target effects in autophagy, metabolism, and glucose uptake. This prompted development of inhibitors that target all forms of p38, such as BIRB-796, or compounds that are selective toward one specific p38 kinase, such as VX-745, a selective p38α inhibitor. The number of isoform-specific p38 inhibitors has since increased, including VX-702, MW-108, MW-181, SCIO 469, and BMS 582949 targeting p38α (see Table 2). Development of isoform-specific compounds was based on more targeted inhibitor design strategies. Nevertheless, non-specific effects of pharmacological p38 kinase inhibitors on other kinases or off-target effects, demand more specific targeting of individual p38 kinases.

Gene Targeting Approaches

Genetic modification of individual p38 genes has been instrumental in uncovering non-redundant functions of individual p38 kinases (Table 3). Two main strategies have been employed: (1) conventional gene targeting in mice to generate complete or conditional knockout alleles for p38α, p38β, p38γ, p38δ. Global deletion of p38 genes in mice results in viable offspring, with the exception of complete p38α knockout, which results in embryonic lethality due to placentation defects. (2) Gene editing approaches using the CRISPR-Cas system to target p38 genes in cells or mice.

RNA Interference

Expression of siRNA or shRNA targeting p38 transcripts offers a feasible solution for reducing p38 levels when neither kinase inhibitors nor genetic alteration on the DNA levels is possible or desired. RNA interference has been used for all p38 transcripts in the past and offers gene-specific reduction in p38 transcript and protein levels. Cell type-specific or brain region-specific isoform-selective RNA interference likely will see increased use to explore functions of p38-regulated pathways in vivo in future studies.

Protein Variants of p38

Constitutively active (CA) variants of all human p38 kinases have been engineered by targeted codon exchanges in the coding sequences. For example, exchange of the Asp-179 to Alanine residue in the activation loop in p38γ results in increased kinase activity, likely due to enhanced engagement with upstream activating kinases. In addition to codon exchanges near the activation loop, CA variants for p38α and p38δ have been generated by single residue exchange at Tyr-323, a region that is associated with tyrosine kinase-mediated p38α activation by ZAP-70. CA variants have been used in cell culture to study effects of downstream target phosphorylation or of increased kinase activity itself. p38CA expression by viral vectors or through transgenesis can be employed to address functions of p38 kinases and their activity in primary cells, organ culture or in vivo. Dominant negative (DN) variants of p38 can be generated by mutations in the activation loop changing the dual phosphorylation motif into Ala-Gly-Phe, which cannot be phosphorylated and activated by upstream kinases. This approach has been used to study function of p38α in mice using a transgenic or knock-in approach.

New biochemical methods to label protein interactions and substrate engagement facilitate mapping of entire MAP kinase signaling cascades. In summary, the molecular and genetic toolbox outlined above, including inhibitor molecules, gene knockout, CRISPR, RNAi, constitutively active (CA) p38 variants, and proximity labeling, facilitated the discovery of functions of p38 kinases and will be essential for future advances toward a better understanding of p38 kinases in CNS cell types and diseases.

Neuronal Functions of p38 Kinases

Of the four p38 kinases, p38α has most extensively been studied in the context of the central nervous system (Figure 2). Neuron-specific functions of p38α are mediated through a multitude of neuronal molecules, some of them central to the roles of this cell type such as ion channels, neurotransmitter receptors, cytoskeletal and adhesion molecules. p38α is expressed in CNS neurons, where it localizes to soma, neurites and synapses. p38α is found at lower levels than other p38 kinases in neurons (i.e., p38β and p38γ. Similar to its function in other cell types, p38α regulates the translation machinery in neurons through downstream regulation of MAP kinase-activated protein (MAPKAP) kinases and mRNA stability. MAPKAP kinases, including MAPKAPK2, phosphorylate Tristetraproline to regulate mRNA stability through adenine/uridine-rich elements. However, the identity and extent of target mRNAs downstream of p38α and MAPKAP kinases in neurons remains to be determined.

Long-Term Potentiation and Depression

Central mechanisms of synaptic plasticity are long-term potentiation (LTP) or long-term depression (LTD), i.e., the activity-dependent up- or downregulation, respectively, of AMPA-type glutamate receptors (AMPARs) at the post-synapse. This receptor reorganization is followed by increased or reduced excitatory currents and consequently an enhancement or reduction in synaptic strength. p38 is involved in regulation of glutamate neurotransmission at post-synaptic neurons (Figure 2B). Activity of p38α is modulated downstream of NMDA-type glutamate receptors (NMDARs), and activation of p38α inversely correlates with the number of AMPA receptors (AMPARs) at synapses upon engagement of NMDARs. These findings implicate p38α in regulation of post-synaptic NMDAR signaling and AMPAR trafficking. Regulation of synaptic plasticity appears to be an evolutionary conserved function of p38. In the nematode Caenorhabditis elegans, trafficking of glutamate receptor GLR-1 is altered in pmk-1 (p38 MAPK) and sek-1 (MAPKK) mutants, which display greater GLR-1 internalization in neurons. In addition, increasing age of nematodes lowers p38 levels and reduces GLR-1 in membranes, which can be restored by increasing p38 levels. This is consistent with work in other model organisms suggesting that p38 promotes AMPAR downregulation and short- and long-term depression.

p38α inhibits NMDAR-mediated LTP. Experimental stimulation of NMDARs results in inactivation of p38 and relieves inhibition of NMDAR-mediated synaptic AMPAR expression. NMDARs engage – at least in part – a pathway through calcium-activated/calmodulin-dependent protein kinase II (CamKII) that activates and SynGAP-MUPP1 that inhibits p38α, respectively. This inhibition of p38α activity is concomitant with dephosphorylation of SynGAP, a negative regulator of Ras-Raf-MEK-ERK signaling. Interestingly, SynGAP knockout neurons show reduced AMPAR surface expression and yet lower p38 activation suggesting that p38 activity is either required for AMPAR surface presentation or other SynGAP-modulated pathways (deregulated in SynGAP knockout cells) have a dominant effect over lower p38 activity. Inhibition of LTP formation is mediated through p38α in different models when LTP is inhibited by angiotensin-II, oligomerized amyloid-beta peptides, or interleukin-1beta. Genetic ablation confirmed a specific involvement of p38α in inhibition of LTP formation by amyloid-β peptides. Thus, evidence from multiple experimental strategies corroborate p38α as a negative regulator of LTP formation.

p38α has been implicated in the induction of LTD in different model systems. p38α enhances LTD in the rat hippocampus/dentate gyrus. In this context, p38α is activated downstream of group I metabolic glutamate receptors (mGluR1/5) through a mechanism dependent on small GTPase Rap1, leading to Rab5-mediated AMPAR internalization and LTD formation in hippocampal neurons. A key downstream target of p38α in LTD is Rab5, a GTPase critical for the endocytic cycle of AMPARs. The protein tyrosine phosphatase STEP is inhibited downstream of mGluR1/5. STEP can directly dephosphorylate and hence deactivate p38α. STEP deactivation can also be mediated by extrasynaptic NMDA receptors through calcium entry, which confers inhibition of LTP and induction of LTD. STEP is itself of therapeutic interest. Regulation of STEP is involved in LTP deficits in a mouse model of fragile X syndrome and mouse models of AD. The effects of modulated STEP activity though may be mediated through a multitude of pathways other than p38α. STEP is required for calcium homeostasis due to increased calcium levels and CamKII activation in hippocampal neurons from STEP-deficient mice, suggesting STEP is an inhibitor of calcium-mediated signaling and neurotransmitter release.

Whether ionotropic properties of NMDA receptors or calcium-independent downstream signals are important for p38-mediated LTD is, however, unclear. Experiments with alterations in extracellular calcium suggest ionotropic NMDAR function is critical to activate p38α downstream of NMDA receptors. However, LTD and dendritic spine shrinkage within a short timeframe could be induced through p38 activation downstream of NMDA receptors despite a complete blockage of NMDA receptor channel properties, suggesting that there are additional mechanisms to activate p38 during LTD enhancement that are independent of NMDAR-mediated calcium currents. The calcium-dependent activation of p38 through NMDARs requires neuron-specific factors such as PSD-95 and neuronal nitric oxide synthase (nNOS). The interaction of nNOS with the NMDAR promotes p38 activation and neuronal excitotoxicity, a mode of toxicity driven by excessive glutamate release/stimulation.

Synaptic plasticity is considered a neuronal proxy of memory consolidation or extinction. Although experiments using cultured brain tissue slices or isolated primary neurons supported a critical role of p38α in LTP inhibition and LTD induction, mice with neuron-specific deletion of p38α did not show altered or impaired memory function.

Regulation of Ion Channels

p38α has been implicated in modulating neuronal excitability through direct action on sodium channels (Figures 2C,D). p38α phosphorylates Ser-553 in L1 region of voltage-gated sodium channel Nav1.6. This phosphorylation event reduces sodium current amplitude through Nav1.6 channels. p38α regulates channel Nav1.8 modulation by phosphorylation, which increases current density in dorsal root ganglion neurons. Voltage-gated sodium channels Nav1.6 and Nav1.8 are widely expressed. Therefore, p38α-mediated sodium current modulation may be applicable to a variety of neurons involved in different brain regions and cognitive functions. In fact, p38α colocalizes with Nav1.6 in cerebellar Purkinje cells and is found in a complex with Nav channels in lysates from rat brain. This association of Nav channels with p38α may serve as a fast-acting regulatory mechanism when Nav channel currents need to be moderated. Consistent with this concept, Nav channel blocker riluzole increases p38 activation in hippocampal neurons. Whether genetic ablation of neuronal p38α sufficiently disrupts regulation of Nav channels, resulting in lower voltage-gated currents and further downstream effects (e.g., on action potentials and neuronal network synchronicity) remains unclear. Multiple kinases have been reported in regulation of Nav channels. Hence, redundancy among kinases in their action on Nav channels could mask phenotypes of individual genetic deletion of p38α.

p38α regulates excitability and ion currents in neurons through other channels. Based on results from neuronal PC12 cell line, NCX1-3 sodium/calcium exchange channels, which are required for maintenance of baseline calcium levels in neurons after excitation is under partial transcriptional control of p38 pathway.

In primary sensory neurons, the transient receptor potential cation channel subfamily V member 1 (TRPV1) channel levels in the plasma membrane are increased by NGF in a p38-dependent manner. This function of p38α may be present in other CNS neurons as TRPV1 is found in the hippocampus, where they impact synaptic plasticity and memory function. TRPV1 channels were also reported to activate p38 once engaged by noxious stimuli (e.g., capsaicin). This may be a positive feedback loop that enhances TRPV1 levels and thus augments noxious signal transmission and nociception.

Synaptic Development

Evidence from nematode studies suggests that p38 signaling may have a function in development of the presynapse. Presynaptic development requires suppression of a pathway consecutively involving DLK1, MKK4 and p38 (pmk-3) downstream of the RING ligase rpm1. This may be accompanied by changes in synaptic mRNA stability and translation downstream of the DLK1-p38-MAPKAP kinase pathway. Interestingly, p38 targets Rab5 in the context of ciliogenesis in the nematode. Rab5 mediates effects of p38α in LTD formation in mammalian cells. Thus, this conserved function in nematode dendritic ciliogenesis may relate to mammalian synaptic plasticity. However, the identity of the MAP kinases activated downstream of DLK may differ between invertebrate and mammalian neurons. In mammalian neurons, the DLK pathway has been linked to post-synaptic neurotoxic, axonal injury stress signaling, where DLK engages JNK downstream rather than p38, and to neuronal migration.

Synaptic Adhesion

p38 kinases are involved in synaptic adhesion molecule expression in neurons (Figure 2B). N-cadherin – a key neuronal homotypic cell–cell adhesion molecule regulating hippocampal spine density and vesicle turnover at neuronal synapses – is downregulated upon induced neuronal activity through a pathway that involves activation of p38 downstream of TAO2 kinase. Here, p38α is likely the key p38 MAPK involved, based on the use of isoform-specific inhibition in these experiments. Downstream factors of p38 in downregulation of N-cadherin are unknown, yet may involve Rab5 similar to p38-mediated AMPA receptor endocytosis. NMDAR activity induces N-cadherin downregulation through β-catenin. This pathway is (at least partially) reminiscent of the TAO2 kinase-p38α pathway function that was shown to regulate N-cadherin endocytosis upon neuronal activation. Whether p38α regulates spine morphology through N-cadherin surface levels in the hippocampus of living mice remains to be determined.

Neuronal Cytoskeleton

Regulation of cytoskeletal proteins and processes through p38 has been investigated in various cell types. Neuronal targets of p38 kinases associated with the cytoskeleton include proteins of the intermediate filaments, microtubule and actin network (Figure 2C). p38α phosphorylates neurofilament (NF) in neuronal axons. Though the physiologic function of this NF phosphorylation is unknown, phosphorylated NF colocalizes with active p38α in neurons from SOD1 mouse model of ALS and in ALS patient samples. p38 kinases can affect the neuronal microtubule network through several targets. A key target is the microtubule-associated protein tau. p38α, p38β, p38γ, and p38δ phosphorylate recombinant tau simultaneously on multiple sites in vitro. In vitro experiments suggest that the phosphorylation of tau by p38 alters microtubule assembly. p38 kinases may phosphorylate markedly different sites on substrate proteins in cells in vivo than on recombinant protein isolated in the lab. Neuronal expression of constitutively active p38γ results in site-specific phosphorylation at a few sites on tau. p38 kinases may regulate the microtubular cytoskeleton through different pathways than tau. The tubulin glutamate ligase TTLL-4 was shown to be activated by p38 (pmk-1) in ciliated sensory neurons of the nematode C. elegans. Whether p38 kinases regulate microtubule assembly and tubulin glutamylation in mammalian neurons in vivo remains to be determined.

Regulation of the actin cytoskeleton by p38 kinases underlies the functions of p38 identified in neuronal migration. Neuronal migration of gonadotropin-releasing hormone-expressing neurons is mediated through p38α and downstream MAPKAP kinase-Hsp25-mediated regulation of actin dynamics. Despite this function identified in a specific neuronal precursor type, p38s have been implicated more broadly in a signaling network that controls cortical neuron migration. Whether this involvement depends on developmental stage and cortical layer is unclear as is the relevance to gross cortical development or the identity of the p38 kinase(s) involved. Notably, deletion of p38α in forebrain neurons late in development and postnatally does not result in compromised cortical layer microanatomy. Additional systematic studies will be required to address the role of p38 kinases in migration of neuronal precursors or specialized neurons within the CNS of model organisms at different stages of their development.

Axonal Maintenance and Transport

p38 kinases may serve localized roles in the axon of neurons (Figure 2C). Both p38α and p38β have at least partial axonal localization in cultured neurons. Axonal injury experiments in cultured neurons support a function of JNK and p38 activation during axon regeneration. Activation of both MAP kinase classes was regulated at different stages of axonal regeneration. This sequential engagement of JNK and p38 kinase may reflect to some extent the invertebrate JIP1/DLK pathway involved in axonal injury and in physiological functions at synapses. This indicates mammalian diversification of MAP kinase signaling in the axon.

Increasing evidence suggests that p38 kinases are involved in regulation of axonal transport. Kinesin function is inhibited by p38-dependent activation of kinesin light chain kinases. This role of p38 activity in the axon was confirmed in a squid neuron model, a classic experimental system to study axonal transport. Activation of p38 downstream of ASK1 interfered with axonal transport of mutant SOD1 protein, likely worsening symptoms of ALS. These results were recently supported by inhibitor experiments in a mouse model of ALS, suggesting that the p38 kinases involved in axonal transport inhibition is p38α. The p38α inhibitor MW069 restored axonal transport and outgrowth in FUS-expressing motor neurons, supporting again that p38α has an important role in regulation of axonal transport processes, at least under disease conditions. This function of p38α may also contribute to axonal impairments in optic neuropathy. Insights into the role of p38 kinases, and in particular p38α, in axonal transport from inhibitor studies should be further corroborated by future experiments with genetic ablation.

Neurotoxicity and Survival

A bulk of studies based on p38 inhibitor experiments support a central function of p38 kinases in neurotoxic signaling or neurotoxicity in general. Most of this work explored the role of p38 kinases in cultured neurons. Specific inhibition of p38α is neuroprotective in multiple forms of neurotoxicity, while p38β does not mediate neurotoxic signals. This function of p38α may apply across different neuronal cell types. p38α inhibition, for example, protected motoneurons from hypoxia-induced cell death or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuron loss. Excitotoxicity, a complex form of toxicity initiated by excess glutamate levels, is at least in part mediated through calcium- and Rho GTPase-mediated activation of p38α, resulting in excitotoxic cell death of cultured neurons. Prions (PrpSc) and prion-like amyloid-beta oligomers mediate some of their neurotoxic effect in cultured hippocampal neurons through a mechanism that involves NMDA receptor, calcium and p38 activation. This is partially reminiscent of excitotoxic signaling and these modes of neurotoxicity show substantial overlap in signaling molecules involved, e.g., downstream of NMDA receptors. Hence, many pathways that mediate NMDA receptor-mediated synaptic plasticity are also involved in glutamate excitotoxicity. Upstream factors of p38 in synaptic plasticity, such as nNOS, calcium, STEP, Rho, and Rab5 affect the role of p38 in glutamate toxicity (Figure 2B). Other experimental methods used to induce glutamate-dependent excitotoxicity have included blocking inhibitory neuron function [e.g., by blocking GABA receptors or engaging kainic acid (KA) receptors] with KA to induce seizures. Our systematic study of different p38 knockout mice, including neuron-specific p38α knockout mice, using PTZ-induced glutamate toxicity as model, did not find involvement of p38α, however, found p38γ is important in suppression of glutamate toxicity.

NMDA receptor-mediated glutamate toxicity involves tau-dependent recruitment of Fyn kinase into a complex of NMDA receptor with scaffolding factor PSD-95. PSD-95 serves as a postsynaptic hub for protective and toxic signaling cascades. Fyn kinase phosphorylates NMDAR subunit NR2B on Tyrosine-1472, which aggravates excitotoxicity. This pathway is inhibited by p38γ, which localizes to post-synapses and binds to PSD-95 through a PDZ domain interaction. p38γ phosphorylates dendritic tau on Threonine-205, which abolishes a complex of PSD-95, tau and Fyn kinase. Therefore, p38γ has a neuroprotective function in excitotoxicity and in other related forms of neurotoxicity such as amyloid-β exposure. Whether p38γ protects neurons from other noxious stimuli and whether these functions of p38γ are all mediated through tau phosphorylation remains to be determined. Thus, depending on context – p38 kinases can have roles that promote survival of neurons and are likely linked to physiologic mechanisms e.g., for p38α or p38γ in NMDA receptor signaling. p38α was shown to promote neuronal survival in culture as a downstream factor of Rit GTPase and proliferation of cerebellar granule neuron precursor. Overall however, neuron-specific p38α or global deletion of p38β, p38γ, p38δ did not result in different neuronal numbers under physiological conditions. Effects of p38 kinases in neurotoxicity or -protection become apparent upon exposure to noxious stimuli. Thus, studies in cultured neurons should be systematically translated to KO models to confirm relevance of the findings. Consistently, a rigorous approach supports a central function of JNK in neuronal apoptosis following excitotoxic insult rather than p38α. Deletion of neuronal p38α or global deletion of p38β, p38δ did not result in altered susceptibility to excitotoxicity in mice. Deletion of p38γ aggravates glutamate toxicity, and neuron-specific transgenesis of CA p38γ protects mice and cells from excitotoxicity, reflecting the protective function of p38γ. Notably, neuron-specific CA p38γ transgenic mice show no obvious cognitive or behavior phenotypes. Thus, depending on context, neuronal p38 kinases serve signaling functions that contribute to resolution of stress through their activity.

Functions in Neuronal Subtypes

p38 kinases have specific functions in neuronal subtypes. Though the functions of individual p38 kinases have not been studied across many different neuron types, there are outstanding examples in specific neuron classes.

Mice that express a dominant negative (DN) variant of p38α in neuronal progenitors show slower age-dependent decline in neurogenesis and context-dependent fear conditioning. p38α was shown to regulate proliferation in peripheral cell types, including hepatocyte and hematopoietic precursor cells. Effects on proliferation are mediated through JNK, MAP kinase-activated protein kinase-2 (MK2), and p53, yet neuronal precursor mechanisms have not been explored.

A study employing targeted deletion of p38α in serotonergic neurons elegantly showed that p38α is required for stress resilience, a protective mechanism in depression and addiction. p38α controls serotonin (5HT) levels in 5HT neurons in the dorsal raphe nucleus (DRN) by phosphorylation and trafficking of the serotonin transporter (SERT). Whether other p38 kinases expressed in 5HT neurons can phosphorylate SERT has not been addressed. This action of p38α results in differential 5HT re-uptake and modulation of serotonin involved in behavior related to anxiety or depression. This mechanism is present in 5HT neurons across different brain regions. In the ventral striatum, SERT serotonin uptake is modulated upon stress exposure, which was shown to activate p38α downstream of κ-opioid receptors resulting in increased SERT cell surface expression. 5HT cells in the dorsal raphe nucleus respond to exposure of rodents to stress with activation of κ-opioid receptors and p38α. Consistently, 5HT neuron specific deletion of p38α or administration of p38α inhibitor (MW150) restores phenotypes of a SERT mutant mouse model of social defeat stress, and pan-neuronal deletion of p38α resulted in reduced resilience to novelty stress and an altered anxiety response. Pan-neuronal p38α-deficient mice had increased activity of JNK in the forebrain and stress response in these mice was restored by inhibition of JNK. These pan-neuronal effects are likely to occur in combination with effects of p38α activity in serotonergic neurons to achieve tailored responses to aversive stimuli and stress.

Similarly, p38α acts in dopaminergic neurons to regulate aspects of behavioral inhibition. κ-opioid receptor engage p38 activation in DA neurons of the ventral tegmental area (VTA) and this pathway is critical in VTA DA neurons for regulating aversive behavior. Given the similarities between DA and 5HT transporters, these effects are potentially regulated through targeting of DA transporter trafficking and function by p38.

In addition, p38 controls DA neuron survival and resistance to oxidative stress. p38 activity downstream of ASK1 is inhibited by klotho, a factor that prevents premature aging and striatal DA neuron loss and promotes remyelination. Thus, inhibition of p38 by klotho may underlie protection from striatal DA neuron loss. Activation of ASK1 is controlled by calcium through binding and inhibition by the calcium-binding protein CIB1 through direct interaction. ASK1 is a key upstream activator of p38 kinases in oxidative stress signaling in multiple cell types. Therefore, toxicity mechanisms that engage the ASK1-p38 pathway in DA neurons may depend on generation of reactive oxygen intermediates. Specific functions of other p38 kinases present in DA neurons are unknown, yet at minimum p38β can be activated downstream of ASK1. Systematic investigation of expression and function of p38β and p38γ in DA neurons may contribute to our understanding of p38-dependent mechanisms in this neuron type.

p38 kinases were shown to be involved in basic mechanisms within clock neurons that regulate diurnal rhythms in organisms across phyla. Fruit flies deficient in p38b or overexpressing p38b in clock neurons showed opposite arrhythmic circadian behavior. p38b controls period gene expression programs in clock neurons through downstream transcription factor Mef2 – an established nuclear target of p38 – and kinase MNK. In vertebrates, active p38 was detected in pineal gland neurons, suggesting p38 kinases are involved in circadian periodicity. It is unclear how p38 kinases are involved in neurons in controlling the circadian rhythm in the mammalian brain. Studies in p38 knockout mice may inform whether lack of p38 kinases affects gross circadian rhythms in terms of activity, sleep, and metabolism.

Neuronal Differentiation

Apart from functions in specific neuron types, p38 kinases contribute to the control of neuronal differentiation and transdifferentiation. Transdifferentiation of sympathetic neurons into cholinergic neurons was shown to be regulated by p38α and p38β in vitro. Experiments with neurospheres derived from adult hippocampal neural stem cells suggest that p38α controls neuronal differentiation and inhibition of p38α maintains pluripotency of progenitor cells. However, p38 kinases appear dispensable for initial differentiation into neuronal cell types in vivo. Neuronal knockout of p38α and global knockout of p38β or p38γ does not result in gross reduction of neuronal numbers. These results may, however, not be conclusive to p38α function for early neuronal differentiation processes in embryogenesis due to timing and restriction of cre recombinase expression. However, experiments in cultured cells have produced conflicting results. p38α-deficient multipotent embryonic stem cells can undergo induced differentiation into neurons, suggesting p38α is dispensable for neuronal differentiation, potentially based on compensation by other p38 kinases. Other results support that differentiation from murine embryonic stem cells is partially dependent on p38α and transcriptional control of bcl2. NGF promotes neuronal differentiation through Rin GTPase and p38α. Inhibition of p38α may indirectly contribute to efficient differentiation through supporting survival of differentiating neurons. Future studies should explore whether there are indeed non-redundant pathways dependent on p38 kinases in neuronal differentiation processes that are not solely related to stress signaling or confounding factors in cultured system. More systematic single neuron analysis with early or global ablation of p38 genes may give a broad picture of roles of these kinases in differentiation in the developing brain.

Astrocytic Functions of p38 Kinases

While much work has focussed on neurons, the p38 family of MAP kinase has important functions in astrocytes. Astrocytes contribute to synaptic transmission by clearance of neurotransmitters, neurotransmitter metabolism and provide structural components of the tripartite synapse architecture, which is made up of a pre-synaptic, a post-synaptic neuronal as well as an astrocytic component in the mammalian central nervous system. Thus, functions of signaling pathways in astrocytes can be relevant to cognition, memory, behavior, development and disease states of the CNS. At least p38α and p38β are present in astrocytes. However, systematic expression studies of all four p38 kinases in astrocytes during resting and stimulated conditions are missing.

p38α regulates astrocytic neuroinflammatory responses during brain injury or neurotoxic insults (Figure 3A). Astrocytic expression of p38α increases upon excitotoxic stress using kainic acid. Both inhibitor studies and genetic ablation of p38α suggest that p38α promotes cytokine and chemokine production during CNS inflammation. Deletion of p38α in astrocytes using a Gfap2-driven cre deleter mouse strain resulted in an altered immune response in the brain and modulated the activation state of astrocytes. Interestingly, JNK activation in p38α-deficient astrocytes was enhanced. This is consistent with reports of JNK inhibition by p38α in other cell types including hepatocytes and neurons. Furthermore, p38α enhances NFκB and MK2 signaling as well as production of reactive oxygen species in astrocytes, which are required for cytokine production downstream of p38α in astrocytes and other cell types. Interestingly, deletion of p38α in astrocytes resulted in fewer activated astrocytes, yet increased influx of activated microglia and peripheral immune cells into sites of CNS inflammation, suggesting that astrocytic p38α regulates recruitment of glial and immune cells, likely through regulation of chemokine release. Consistent with differential roles of p38α in astrocytes and microglia, p38α can affect mounting and resolution of peripheral inflammatory processes differently through its action in different cell types.

p38α was shown to regulate serotonin metabolism in serotonergic neurons, impacting on anxiety and addiction behavior. This function of p38α in 5HT neurons is enhanced by astrocytic p38α, which regulates serotonin uptake into astrocytes. Future studies may want to address whether p38α regulates uptake and metabolism of other neurotransmitters in astrocytes.

p38β regulates cell survival of astrocytes by protecting them from apoptosis. Kainic acid induces different kinetics of expression of p38β compared with p38α in astrocytes based on immunoreactivity. The protective function of p38β in astrocytes may be related to this difference in expression, yet detailed signaling events involved in this function of p38β are unknown.

Microglial Functions of p38 Kinases

Microglia express all four p38 kinases, and microglial p38 kinases have partially overlapping as well as redundant functions (Figure 3B). Inhibitor and gene knockout studies imply p38 and downstream pathways in mediating neuroinflammation in multiple contexts and models.

p38 kinases regulate microglial activation upon exposure to proinflammatory cytokines and amyloid-β or during tissue injury. Microglia-specific deletion of p38α (using Cx3cr1-cre delete) reduces inflammatory reaction, cytokine levels, and microglial recruitment to damaged brain regions in a mouse model of traumatic brain injury. Results from lysozyme promoter-driven p38α deletion in myeloid cells that partially contribute to microglia populations resulted, however, in increased levels of cytokines during acute injury-related inflammation. Cytokine production from microglia is regulated downstream of p38α by MK2. Thus, p38α and downstream pathways have an established role in microglial cytokine production. p38α may indeed be a key p38 kinase in microglial activation. A study suggested p38β is not involved in microglia activation.

p38α regulates additional aspects of microglial biology. p38α inhibits autophagy in microglia by phosphorylation of ULK1. Autophagy in microglia was shown to inhibit inflammatory response. In these experiments, microglia lacking p38α were found to release more cytokines, similar to acute inflammatory response in p38α-deficient microglial cells.

Microglia release exosomes, a mechanism that is important in brain physiology and for spreading of pathology in neurodegenerative diseases. Release of microparticles and IL-1β from microglia downstream of sphingomyelinase activity was shown to be p38-dependent based on an inhibitor that targets p38α and p38β. SB203580, the inhibitor used in this work, has been, however, shown to affect autophagy and therefore may affect vesicle trafficking and release. Thus, studies in p38 knockout microglia are needed to clarify the role of p38 kinases.

p38 kinases can regulate neuroprotective pathways through their action in microglia. The neuroprotective biacetophenone cynandione A was shown to induce microglial β-endorphin expression, which was blocked by knockdown of p38β. Microglia-derived β-endorphin dampens nociceptive stimuli through a mechanism that involves glucagon-like peptide-1 receptors. These results suggest that p38β has a function in modulation of nociceptive sensory systems.

p38 kinases in microglia may have isoform-specific functions downstream of different receptors. p38β acts downstream of glucagon-like peptide-1 receptors. p38δ was shown to act downstream of the ATP receptors P2 × 7 in microglia, enhancing the release of IL-1β and inflammation within the spinal cord. It will be interesting to explore interaction partners and engagement in distinct signaling pathways for different p38 kinases downstream of microglial surface receptors. Molecular determinants within the primary sequence of the four p38 kinases that would support mechanistic engagement with specific receptor complexes are unknown. An exception is p38γ, which carries a C-terminal PDZ interaction motif to recruit p38γ into complexes in neurons and other cells based on interaction with cognate PDZ domain-containing proteins.

Functions of p38 Kinases in Myelinating Cells

p38 kinases regulate aspects of myelinating cell function (Figure 3C). Differentiation of oligodendrocytes in vivo is controlled by the p38α-MK2 pathway through downstream effects on transcription factor cAMP response element binding protein (CREB). However, genetic deletion of p38α in oligodendroglia, using the NG2 cre delete strain, resulted in no gross myelination deficits, albeit delayed oligodendrocyte differentiation, alterations in the ultrastructure of myelin, and delayed myelination in the corpus callosum. Deficiency in oligodendroglial p38α has no effect on myelination when inducing demyelination with LPS or oxidative stress yet enhances remyelination after cuprizone-induced demyelination. Consistent with these results genetic heterozygosity in p38α improves recovery in an animal model of spinal cord injury. This function of p38α is relevant to the peripheral nervous system as well. Mechanistic studies in Schwann cells with genetic deletion of p38α support that p38α limits myelination and showed accelerated myelination by p38α-deficient Schwann cells postnatally. This function of p38α is partially mediated through transcriptional control of Krox-20, a master transcription factor in Schwann cells.

Functions of p38 kinases other than p38α in myelinating cells are less well characterized. The homolog of the disks large Dlg1, a MAGUK family member that has an inhibitory function in myelination of the peripheral system, undergoes post-translational modification downstream of Kif13b, a kinesin-like factor regulating intracellular localization of MAGUKs. Dlg1 forms a complex with KIF13B and p38γ, is then phosphorylated by p38γ and subsequently ubiquitinated. These modifications in response to KIF13B activity reduce cellular levels of Dlg1 and result in enhanced myelinating function of Schwann cells. Addressing sciatic nerve myelination, this study found reduced myelin sheath thickness in p38γ knockout nerves, yet normal axonal numbers and fiber diameter. Whether the same mechanism regulates myelinating cells of the central nervous system remains to be determined. Nevertheless, the impact of p38γ on Dlg1 in CNS myelination processes may be limited to specific stimuli and/or non-physiological conditions because global knockout of p38γ does not result in gross myelination defects in white matter tracks of mice. The p38γ – Dlg1 pathway may potentially have different functions in oligodendrocytes as Dlg1 acts to promote myelinating function of cells through a pathway involving PTEN-dependent inhibition of Akt (v-AKT murine thymoma viral oncogene homolog) activity. Thus, p38 kinase function in myelinating cells of the peripheral and central nervous system differ.

p38 Kinases in Other CNS Cell Types

p38 kinases are involved in functions of additional cell types present in the CNS, including endothelial cells and pericytes, and contribute to neuroinflammation and control of the cerebrovasculature and blood–brain-barrier (BBB). p38 activation promotes experimental BBB disruption, which is inhibited by TGF-β-induced expression of MKP1. TGF-β1 and p38 MAP kinase reciprocally regulate pericyte expression of MMP-9. This suggests p38 signaling pathway involvement in regulation of neurovascular homeostasis under conditions of stress exposure.

Roles of p38 Kinases in Cognitive Functions

p38 is activated by stress stimuli in cells. Deletion of p38 genes – with the exception of p38α – does not result in obvious changes in cognition or behavior of mice under resting conditions. Even ablation of p38α in neurons, astrocytes or microglia does not result in apparent basal changes. Several key functions of p38 kinases in cognition became evident with challenge from drugs, cognitive tasks or psychogenic stress.

Anxiety

p38α deletion in neurons results in increased anxiety tested by open field paradigm and elevated plus maze (Figure 4A). Grehlin, a gastric peptide with anxiolytic activity in the brain, was shown to require p38 activity based on inhibitor injection into hippocampus. p38α in serotonergic cells of the Raphe nucleus is necessary for SERT membrane expression and 5HT re-uptake induced by chemical/environmental stressors, reducing serotonin-modulated behaviors. Activated p38α in presynaptic VTA neurons phosphorylate GIRK Kir3.1 to decrease somatic excitability and exocytosis of dopamine, allowing for development of place aversion in a behavioral conditioning task. Anxiety-related behavioral phenotypes are not apparent in p38γ knockout mice and have not been addressed for in p38β or p38δ knockout mice.

Addiction Behavior

p38 regulates drug seeking behavior, based on mouse models of addiction (Figure 4A). Cocaine application activated p38 in nucleus accumbens and prefrontal cortex, and results in recruitment of active p38 to norepinephrine transporter (NET) and DA transporter (DAT). p38 can phosphorylate NET at Thr-30 and blocking this interaction in mice reduced cocaine-conditioned place preference in mice. Furthermore, morphine-conditioned place preference was not affected by p38 inhibition, suggesting a cocaine-specific engagement of p38 in this behavior. Interestingly, this study suggests that amphetamine – a drug of addiction that targets the serotonergic system – selectively induces p38 association with SERT, confirming previous findings of regulation of SERT and addiction behavior mediated through serotonergic neurons. κ-opioid receptors regulate drug reinstatement in rat models of cocaine self-administration. This action of κ-opioid receptor signaling is dependent on p38. Ablation of p38α serotonergic neurons or astrocytes lower reinstatement of cocaine preference, providing genetic evidence for a significant role of p38 – and in particular p38α – in addiction.

Learning and Memory

Memory tests in neuron-specific p38α knockout mice revealed no deficits in memory acquisition or retrieval at 6–8 months of age (Figure 4A). Contextual fear condition DN p38α knock-in, in which the activation motif is mutated to Ala-Gly-Phe, mice show enhanced performance. DN p38α mice were significantly protected from age-dependent reduction in hippocampal adult neurogenesis. This suggests that p38α regulates aspects of memory function through inhibiting neurogenic precursor function. Thus, evidence suggest that p38 kinases have limited impact on memory acquisition. However, downstream substrates of p38α/β, MAPKAP kinases 2 and 3, are important for AMPAR endocytosis during long-term depression and regulate cognitive flexibility in spatial memory tasks. Other p38 kinases such as p38γ or p38δ appear dispensable for physiologic memory function. Knocking out p38γ or increasing activity of neuronal p38γ results in not alteration of memory function in mice, even at advanced age (unpublished results).

p38 Kinases in CNS Disorders and Neurodegeneration

p38 kinases have been linked to several neurological disorders, in particular, when associated with neuroinflammatory responses. This is largely based on their prominent role in cytokine production and release from immune cells including microglia. Despite this role in neuroinflammation, distinct involvement of individual p38 kinases in pathways in different types or even sub-types of cells of the nervous system make contributions to disease processes. This is either through physiologic, protective mechanisms that dampen disease development or by enhancing disease progression through promoting toxic signaling.

Ischemia

Ischemic conditions are associated with multiple neurological disorders, including stroke, brain injury and involves multiple secondary responses such as hypoxic response, neuroinflammation and excitotoxicity. p38 becomes activated by hypoxic conditions in brain tissue. Involvement in ischemia-induced neurologic disorder has been largely addressed by inhibitor studies. Inhibition of p38α and p38β in ischemic conditions lowers neuroinflammation and cytokine release (Figure 5A). Work in cultured cells showed that p38α and p38γ are activated by hypoxia rather than p38β or p38δ and p38α is required for hypoxia-induced factor-1 (HIF-1) stabilization. Whether p38α and/or p38γ are critical for hypoxic response in CNS cells remains to be determined, yet it may suggest that p38α and p38γ could be specific targets for treatment of brain ischemia. Understanding the function of these 2 kinases in different brain cell types will be required as hypoxia induces p38 activation in both neurons and microglia. Phosphatase STEP interacts with and reduces activation of p38, lowering neurotoxicity in ischemia models. Promoting activity of STEP toward p38 is neuroprotective and reduces infarct size. Furthermore, p38α in astrocytes is responsive to hypoxia and astrocyte-specific deletion of p38α results in lower inflammatory responses, astrocyte recruitment and activation in a model of ischemic stroke.

Traumatic Brain Injury

p38α regulates neuroinflammation during traumatic brain injury (Figure 5A). Microglia-specific deletion of p38α protects mice in a model of traumatic brain injury or LPS-driven neuroinflammation, lowering activation of microglia, influx of peripheral inflammatory cells, synaptic loss and ameliorates motor impairments. Both the involvement of p38 (foremost p38α) in neuroinflammation during TBI is largely based on the function of the p38α-MK2 pathway in cytokine production. Consistent with the prominent role of p38α in microglia in promoting TBI, inhibition of p38α and p38β had no effect on injury in a neuronal culture model. However, this early study did not find an effect of p38 inhibition by p38α/β-specific inhibitor SB203580 on the lesion size or motor performance after cerebrocortical injury. These results indicate cell-type specific contributions of p38 to pathomechanisms in TBI.

Pain

p38 kinases are involved in nociception and neuropathic pain (Figure 5B). Antinociceptive action was found in animal models of pain for p38α inhibitors. Mechanism of action of p38α in nociception are based on regulation of nociceptive channels. Hyperalgesia maintained by p38-mediated TRPV1 levels in sensory neurons. Other p38 kinases have different functions in nociception than p38α. Knockdown of p38β within the spinal cord of rats induced hyperalgesia upon spinal cord injury. Thus roles of p38α in neurons and for p38β in microglia promote hyperalgesia. Other work, however, suggested no involvement of p38β in microglial activation or even a protective effect of microglial p38β from neuropathic pain. Taken together, mechanisms involving p38 kinases in nociception are not extensively understood and may depend on the type and time course of pain stimulus. However, overall evidence supports p38 as drug targets in treatment of pain.

Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, is characterized by specific neurodegeneration within spinal cord, brain stem and cerebrum. Increased activity of stress-activated MAP kinase was detected in cortical neurons of an ALS mouse model while higher p-p38 levels have been detected in human post-mortem ALS brains and mouse models of ALS. Activation of p38 in ALS models is associated with activated upstream kinase ASK1 and markers of apoptosis at an early stage and mammalian sterile-20-like kinase 1 was shown to activate p38 in a SOD1 mouse model (Figure 5C). SOD1 mutations are prevalent in ALS. Inhibition of p38 has protected mutant SOD1 transgenic mice from motor neuron loss. Pathogenic SOD1 inhibits axonal transport in motor neurons through activation of p38α downstream of ASK1. Consistently, p38α inhibition restores retrograde axonal transport in a mouse model of ALS based on expression of mutant SOD1. Thus, p38 MAP kinase - in particular p38α – is a promising therapeutic target in SOD1-associated forms of ALS.

Familial ALS can be associated with other mutations than in SOD1. FUS (fused in osteosarcoma) mutations are linked to familial forms of ALS. Brain tissue from ALS with FUS mutations displayed increased levels of activated p38 and mutant FUS affects axonal transport through p38 activity. These results suggest that p38 activation and downstream effects are a common mechanism in multiple forms of ALS pathogenesis.

Alzheimer’s Disease (AD)

Alzheimer’s disease is the most prevalent form of neurodegenerative dementia and associated with extracellular plaques derived from amyloid-β peptide aggregates and intracellular neurofibrillary tangles, which consist mainly of hyperphosphorylated forms of the neuronal tau protein. Hence, much research has focussed on amyloid-β (Aβ) and tau as central factors in the diseases.

Increased levels of activated p38 has been found in neurons from AD brains and tissue samples from transgenic AD mouse models based on increased expression of pathogenic amyloid-β precursor protein (APP) (Figure 5D). As such, p38 MAP kinase has been suggested as drug target for AD treatment. Aβ can activate p38 in neurons, which may be mediated through NMDA receptors because NMDAR blocker MK801 suppressed p38 activation in APP transgenic mice. Furthermore, p38α – was shown to mediate some of the neurotoxic effects of Aβ, including suppression of long-term potentiation and neuronal death in culture based both on pharmacological inhibition and neuron-specific deletion of p38α. The latter work also found a reduction in Aβ deposition in AD mice crossed with neuron-specific p38α knockout mice resulting in lower amyloid plaque burden. Thus, p38α appears to regulate both toxic signals downstream of Aβ in neurons as well as Aβ processing and/or deposition. p38α affects Aβ processing through regulation of protein levels of the APP-processing protease BACE1 in neurons and through modulation of autophagy, both of which increase the amount of extracellular Aβ. Results from p38α inhibition in microglia, however, suggest that p38α promotes phagocytosis of amyloid-beta by microglia. p38α inhibition also reduces tau pathology, i.e., levels of hyperphosphorylated tau, through increasing autophagy by microglial. Thus, p38α may serve several functions in the context of amyloid and tau pathology. Nevertheless, p38α has been put forward as key drug target in amyloidosis and associated dementia. Experiments with an p38α-specific inhibitor in AD mouse models suggest that this strategy is sufficient to ameliorate Aβ-induced cognitive impairment.

Receptor for advanced-glycation end products (RAGE) was shown to activate p38, resulting in LTP inihibition. Signals through RAGE and p38 may converge on LTP inhibition in AD. Antagonizing RAGE by a dominant negative RAGE receptor in a mouse model of AD prevents p38 activation in the hippocampus, LTP and memory impairment.

p38γ MAP kinase has recently been shown to mediate a neuroprotective function in AD mouse models. p38γ differs from other p38 kinases in harboring a C-terminal PDZ interaction motif, which mediates its localization to the post-synapse. Aβ had previously been shown to mediate its toxic effects through tau, laying the foundation to the concept of the tau-dependent ‘amyloid cascade,’ which links both key factors in a central toxic signaling pathway. Mechanistically, tau, a predominantly axonal protein in neurons, is partially localizing to dendrites where it interacts with post-synaptic scaffolding factor PSD-95 downstream of NMDA receptors. This interaction is required to mediate toxic effects of Aβ in neurons and in mice. p38γ interacts with PSD-95 and was shown to phosphorylate tau predominantly on Threonine-205 in this complex. This phosphorylation event results in disruption of the PSD-95-tau complex and inhibits toxic signals of Aβ. Thus, this mechanism involving post-synaptic p38γ showed a novel neuroprotective function for this p38 kinase and revealed an unprecedented function of tau phosphorylation in inhibiting a pivotal toxicity mechanism of Aβ. Interestingly, neither p38α, p38β nor p38δ were able to mediate the same neuroprotective tau phosphorylation and inhibition of Aβ toxicity as p38γ, likely due to the distinct localization of p38γ in neurons at post-synapses.

Parkinson’s Disease (PD)

Loss of dopaminergic (DA) neurons is a hallmark of PD. p38 activity was found in DA neurons in the substantia nigra pars compacta in PD patient samples and PD mouse models (Figure 5E). Activation of p38 induced nuclear localization of p53 in DA neurons in a MPTP model whereas inhibition of p38 protects DA neurons. In addition, p38 controls DA neuron survival and resistance to oxidative and inflammatory stress. p38 activity downstream of ASK1 is inhibited by klotho, a factor that prevents premature aging and striatal DA neuron loss. A transgenic PD mouse model based on mutant α-synuclein expression presented with activation of p38, which phosphorylates Parkin-1 and promotes mitochondrial dysfunction and DA neuron loss (Figure 5E).

Though loss of DA neurons is the most prominent feature, neuronal dysfunction and degermation is not strictly limited to DA neurons. Serotonergic loss contributes to symptoms and neuropsychiatric changes in PD. This is particularly true for PD associated with mutations in the α-synuclein-encoding SNCA gene. indicate that p38α regulates serotonin release and reuptake through serotonin transporter cell surface trafficking. This function of p38α may be important in serotonergic dysfunction in PD, making p38α a potential drug target for serotonin-associated symptoms of PD.

Huntington’s Disease

Huntingtin (Htt) poly-glutamine expansion is a hallmark of Huntington’s disease. Activated p38 was found in multiple HD models. Poly-glutamine Htt activates p38 MAPK kinase, yet conflicting evidence suggests mutant Htt activates ERK MAP kinase rather than JNK or p38 MAP kinases. However, MAP kinase phosphatase-1 (MKP-1), which specifically deactivates p38 and JNK has a protective function in striatal neurons of a Huntington’s model, suggesting that activity of p38 contributes to toxic signals induced by mutant Htt. Consistently, inhibition of p38α and p38β protects from neurotoxicity induced by polyglutamic.

Spinal Cord Injury (SCI)

p38α plays a central role in inflammatory process in SCI through translation and stabilization of inflammatory mRNAs. For example, MAPKAPK2 or MK2, the downstream kinase of p38, interferes with the interaction between the binding factors and AU-rich elements (AREs) which in turn stabilizes TNF-α mRNA [reviewed in ]. In addition, p38/MK2-induced mRNA stabilization also controls the expression of IL-6 which triggers activation and infiltration of leukocytes in SCI. Thus, p38α can initiate major SCI-related proinflammatory cytokines in the post-traumatic inflammation. Extensive research utilizing various p38α inhibitors and genetically modified mice that p38α plays an important role in various stages of inflammatory process [reviewed in ]. Increased spatial activation of p38α was observed in neurons, oligodendrocytes, microglia/macrophages, infiltrated neutrophils, and reactive astrocytes which formed a glial scar following SCI [reviewed in ]. Activation of p38α in activated microglia/macrophages in SCI models induces iNOS expression, contributing to loss of neuronal cells. IL-1β and p38 phosphorylation was detectable prior to neuronal apoptosis, and IL-1 receptor antagonist and p38 inhibition, suppressed p38 phosphorylation and neuronal apoptosis, indicating a critical involvement of IL-1β/p38α signaling axis in neuronal apoptosis post-SCI.

Conclusion and Future Questions

The last two decades of research have seen p38 kinases move from stress-activated kinases to signal transducers in multiple physiologic and pathophysiologic functions. This is particularly true for cells of the central nervous system, where specific functions of p38 kinases were revealed in all major cell types contributing to brain physiology, cognition and behavior as well as disease processes. These discoveries are attributable to the development of more specific genetic and pharmacologic tools that are able to dissect functions of individual kinases. Development of these tools has made answering the following outstanding questions on p38 in the CNS feasible:

What is the brain region- and cell type-specific expression of individual p38 kinases?

In tissue with co-expression of p38 isoforms, are the kinases functionally distinct or is there redundancy?

Does p38α regulate broadly regulate biogenic amine neurotransmission through parallel mechanisms? Can these mechanisms be targeted to treat disorders associated with specific neurotransmitter systems?

What distinct roles do p38β, p38γ and p38δ have in behavior and cognition?

What is the therapeutic potential of p38α inhibition for treatment of neurodegeneration, addiction, and anxiety? What are the mechanisms of action? Could drugs target the role of p38α in neuroinflammation, autophagy, regulating synaptic plasticity, mediating axonal transport?

What is the therapeutic potential of p38γ for conditions of excitotoxicity and neurodegeneration?

What is the therapeutic potential of p38β in motor neuron disease/ALS targeting its function in microglia?

Investigating mechanisms involving p38 kinases provides new molecular insights into brain physiology and opens new therapeutic avenues to understand and target neurological disorders. From the basis of roles in inflammation by initial discoveries of p38, a more diversified picture of p38 kinase functions is still emerging.

Author Contributions

AI, PA, EP, and KS wrote first draft of the manuscript. PA edited sections of cell-type specific functions of p38 and contributed to preparation of figures. EP edited sections of MAP kinase signaling cascade and prepared figures. KS wrote section of disease-related functions of p38 in CNS. AT and HA edited the manuscript draft and contributed to figure preparation. AI designed concept and outline of the manuscript. All authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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    Borsch-Haubold A. G. Pasquet S. Watson S. P. (1998 ). Direct inhibition of cyclooxygenase-1 and -2 by the kinase inhibitors SB 203580 and PD 98059. SB 203580 also inhibits thromboxane synthase. J. Biol. Chem. 273 28766–28772.

    Not in our library10.1074/jbc.273.44.28766

  34. 34.

    Bosco F. Valente P. Milanese M. Piccini A. Messa M. Bonanno G. (2018 ). Altered Intracellular Calcium Homeostasis Underlying Enhanced Glutamatergic Transmission in Striatal-Enriched Tyrosine Phosphatase (STEP) Knockout Mice. Mol. Neurobiol. 55 8084–8102.

    Not in our library10.1007/s12035-018-0980-5

  35. 35.

    Boulton T. G. Nye S. H. Robbins D. J. Ip N. Y. Radziejewska E. Morgenbesser S. D. (1991 ). ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65 663–675.

    Not in our library10.1016/0092-8674(91)90098-j

  36. 36.

    Brancho D. Tanaka N. Jaeschke A. Ventura J. J. Kelkar N. Tanaka Y. (2003 ). Mechanism of p38 MAP kinase activation in vivo. Genes Dev. 17 1969–1978.

    Not in our library10.1101/gad.1107303

  37. 37.

    Brobey R. K. Dheghani M. Foster P. P. Kuro O. M. Rosenblatt K. P. (2015a ). Klotho Regulates 14-3-3zeta Monomerization and Binding to the ASK1 Signaling Complex in Response to Oxidative Stress. PLoS One 10:e0141968.

    Not in our library10.1371/journal.pone.0141968

  38. 38.

    Brobey R. K. German D. Sonsalla P. K. Gurnani P. Pastor J. Hsieh C. C. (2015b ). Klotho Protects Dopaminergic Neuron Oxidant-Induced Degeneration by Modulating ASK1 and p38 MAPK Signaling Pathways. PLoS One 10:e0139914.

    Not in our library10.1371/journal.pone.0139914

  39. 39.

    Brown T. C. Tran I. C. Backos D. S. Esteban J. A. (2005 ). NMDA receptor-dependent activation of the small GTPase Rab5 drives the removal of synaptic AMPA receptors during hippocampal LTD. Neuron 45 81–94.

    Not in our library10.1016/j.neuron.2004.12.023

  40. 40.

    Bruchas M. R. Land B. B. Aita M. Xu M. Barot S. K. Li S. (2007 ). Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria. J. Neurosci. 27 11614–11623.

    Not in our library10.1523/jneurosci.3769-07.2007

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    Bruchas M. R. Schindler A. G. Shankar H. Messinger D. I. Miyatake M. Land B. B. (2011 ). Selective p38alpha MAPK deletion in serotonergic neurons produces stress resilience in models of depression and addiction. Neuron 71 498–511.

    Not in our library10.1016/j.neuron.2011.06.011

  42. 42.

    Bu X. Huang P. Qi Z. Zhang N. Han S. Fang L. (2007 ). Cell type-specific activation of p38 MAPK in the brain regions of hypoxic preconditioned mice. Neurochem. Int. 51 459–466.

    Not in our library10.1016/j.neuint.2007.04.028

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    Bussi C. Peralta Ramos J. M. Arroyo D. S. Gaviglio E. A. Gallea J. I. Wang J. M. (2017 ). Autophagy down regulates pro-inflammatory mediators in BV2 microglial cells and rescues both LPS and alpha-synuclein induced neuronal cell death. Sci. Rep. 7:43153.

    Not in our library10.1038/srep43153

  44. 44.

    Cai W. Rudolph J. L. Sengoku T. Andres D. A. (2012 ). Rit GTPase regulates a p38 MAPK-dependent neuronal survival pathway. Neurosci. Lett. 531 125–130.

    Not in our library10.1016/j.neulet.2012.10.036

  45. 45.

    Cao J. Semenova M. M. Solovyan V. T. Han J. Coffey E. T. Courtney M. J. (2004 ). Distinct requirements for p38alpha and c-Jun N-terminal kinase stress-activated protein kinases in different forms of apoptotic neuronal death. J. Biol. Chem. 279 35903–35913.

    Not in our library10.1074/jbc.m402353200

  46. 46.

    Cao J. Viholainen J. I. Dart C. Warwick H. K. Leyland M. L. Courtney M. J. (2005 ). The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death. J. Cell Biol. 168 117–126.

    Not in our library10.1083/jcb.200407024

  47. 47.

    Casar B. Sanz-Moreno V. Yazicioglu M. N. Rodriguez J. Berciano M. T. Lafarga M. (2007 ). Mxi2 promotes stimulus-independent ERK nuclear translocation. EMBO J. 26 635–646.

    Not in our library10.1038/sj.emboj.7601523

  48. 48.

    Castillo J. Leira R. Garcia M. M. Serena J. Blanco M. Davalos A. (2004 ). Blood pressure decrease during the acute phase of ischemic stroke is associated with brain injury and poor stroke outcome. Stroke 35 520–526.

    Not in our library10.1161/01.str.0000109769.22917.b0

  49. 49.
    Dual‐specificity MAP kinase phosphatases (MKPs) · 2012
    No notice
  50. 50.

    Cavallini A. Brewerton S. Bell A. Sargent S. Glover S. Hardy C. (2013 ). An unbiased approach to identifying tau kinases that phosphorylate tau at sites associated with Alzheimer disease. J. Biol. Chem. 288 23331–23347.

    Not in our library10.1074/jbc.m113.463984

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    Chamorro A. Dirnagl U. Urra X. Planas A. M. (2016 ). Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol. 15 869–881.

    Not in our library10.1016/s1474-4422(16)00114-9

  52. 52.

    Che Y. Piao C. S. Han P. L. Lee J. K. (2001a ). Delayed induction of alpha B-crystallin in activated glia cells of hippocampus in kainic acid-treated mouse brain. J. Neurosci. Res. 65 425–431.

    Not in our library10.1002/jnr.1170

  53. 53.

    Che Y. Yu Y. M. Han P. L. Lee J. K. (2001b ). Delayed induction of p38 MAPKs in reactive astrocytes in the brain of mice after KA-induced seizure. Brain Res. Mol. Brain Res. 94 157–165.

    Not in our library10.1016/s0169-328x(01)00233-9

  54. 54.

    Chen J. Ren Y. Gui C. Zhao M. Wu X. Mao K. (2018 ). Phosphorylation of Parkin at serine 131 by p38 MAPK promotes mitochondrial dysfunction and neuronal death in mutant A53T alpha-synuclein model of Parkinson’s disease. Cell Death Dis. 9:700.

    Not in our library10.1038/s41419-018-0722-7

  55. 55.

    Chen X. Lin R. Chang L. Xu S. Wei X. Zhang J. (2013 ). Enhancement of long-term depression by soluble amyloid beta protein in rat hippocampus is mediated by metabotropic glutamate receptor and involves activation of p38MAPK, STEP and caspase-3. Neuroscience 253 435–443.

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  56. 56.

    Cheung P. Y. Zhang Y. Long J. Lin S. Zhang M. Jiang Y. (2004 ). p150(Glued), Dynein, and microtubules are specifically required for activation of MKK3/6 and p38 MAPKs. J. Biol. Chem. 279 45308–45311.

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  57. 57.

    Chittajallu R. Vignes M. Dev K. K. Barnes J. M. Collingridge G. L. Henley J. M. (1996 ). Regulation of glutamate release by presynaptic kainate receptors in the hippocampus. Nature 379 78–81.

    Not in our library10.1038/379078a0

  58. 58.
    Dual-Specificity Phosphatase 12 Targets p38 MAP Kinase to Regulate Macrophage Response to Intracellular Bacterial Infection · 2017
    Not checked
  59. 59.

    Chung S. H. Biswas S. Selvaraj V. Liu X. B. Sohn J. Jiang P. (2015 ). The p38alpha mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS. Cell Death Dis. 6:e1748.

    Not in our library10.1038/cddis.2015.119

  60. 60.

    Chung S. H. Biswas S. Sohn J. Jiang P. Dehghan S. Marzban H. (2018 ). The p38alpha MAPK Deletion in Oligodendroglia does not Attenuate Myelination Defects in a Mouse Model of Periventricular Leukomalacia. Neuroscience 386 175–181.

    Not in our library10.1016/j.neuroscience.2018.06.037

  61. 61.

    Clark A. K. Staniland A. A. Marchand F. Kaan T. K. McMahon S. B. Malcangio M. (2010 ). P2X7-dependent release of interleukin-1beta and nociception in the spinal cord following lipopolysaccharide. J. Neurosci. 30 573–582.

    Not in our library10.1523/jneurosci.3295-09.2010

  62. 62.

    Clement S. L. Scheckel C. Stoecklin G. Lykke-Andersen J. (2011 ). Phosphorylation of tristetraprolin by MK2 impairs AU-rich element mRNA decay by preventing deadenylase recruitment. Mol. Cell. Biol. 31 256–266.

    Not in our library10.1128/mcb.00717-10

  63. 63.

    Colie S. Sarroca S. Palenzuela R. Garcia I. Matheu A. Corpas R. (2017 ). Neuronal p38alpha mediates synaptic and cognitive dysfunction in an Alzheimer’s mouse model by controlling beta-amyloid production. Sci. Rep. 7:45306.

    Not in our library10.1038/srep45306

  64. 64.

    Conrad P. W. Rust R. T. Han J. Millhorn D. E. Beitner-Johnson D. (1999 ). Selective activation of p38alpha and p38gamma by hypoxia. Role in regulation of cyclin D1 by hypoxia in PC12 cells. J. Biol. Chem. 274 23570–23576.

    Not in our library10.1074/jbc.274.33.23570

  65. 65.

    Consortium G. T. (2015 ). Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348 648–660.

    Not in our library10.1126/science.1262110

  66. 66.

    Coogan A. N. O’Neill L. A. O’Connor J. J. (1999 ). The P38 mitogen-activated protein kinase inhibitor SB203580 antagonizes the inhibitory effects of interleukin-1beta on long-term potentiation in the rat dentate gyrus in vitro. Neuroscience 93 57–69.

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  67. 67.

    Cortez I. Bulavin D. V. Wu P. McGrath E. L. Cunningham K. A. Wakamiya M. (2017 ). Aged dominant negative p38alpha MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning. Behav. Brain Res. 322(Pt B), 212–222.

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  68. 68.

    Cremer C. M. Palomero-Gallagher N. Bidmon H. J. Schleicher A. Speckmann E. J. Zilles K. (2009 ). Pentylenetetrazole-induced seizures affect binding site densities for GABA, glutamate and adenosine receptors in the rat brain. Neuroscience 163 490–499.

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  69. 69.

    Criscuolo C. Fontebasso V. Middei S. Stazi M. Ammassari-Teule M. Yan S. S. (2017 ). Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer’s disease mouse model. Sci. Rep. 7:42370.

    Not in our library10.1038/srep42370

  70. 70.

    Crown E. D. Gwak Y. S. Ye Z. Johnson K. M. Hulsebosch C. E. (2008 ). Activation of p38 MAP kinase is involved in central neuropathic pain following spinal cord injury. Exp. Neurol. 213 257–267.

    Not in our library10.1016/j.expneurol.2008.05.025

  71. 71.

    Cuadrado A. Nebreda A. R. (2010 ). Mechanisms and functions of p38 MAPK signalling. Biochem. J. 429 403–417.

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  72. 72.

    Cuenda A. Rouse J. Doza Y. N. Meier R. Cohen P. Gallagher T. F. (1995 ). SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett. 364 229–233.

    Not in our library10.1016/0014-5793(95)00357-f

  73. 73.

    Cuenda A. Rousseau S. (2007 ). p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim. Biophys. Acta 1773 1358–1375.

    Not in our library10.1016/j.bbamcr.2007.03.010

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    Culbert A. A. Skaper S. D. Howlett D. R. Evans N. A. Facci L. Soden P. E. (2006 ). MAPK-activated protein kinase 2 deficiency in microglia inhibits pro-inflammatory mediator release and resultant neurotoxicity. Relevance to neuroinflammation in a transgenic mouse model of Alzheimer disease. J. Biol. Chem. 281 23658–23667.

    Not in our library10.1074/jbc.m513646200

  75. 75.

    Da Silva J. Pierrat B. Mary J. L. Lesslauer W. (1997 ). Blockade of p38 mitogen-activated protein kinase pathway inhibits inducible nitric-oxide synthase expression in mouse astrocytes. J. Biol. Chem. 272 28373–28380.

    Not in our library10.1074/jbc.272.45.28373

  76. 76.

    Dai H. L. Hu W. Y. Jiang L. H. Li L. Gaung X. F. Xiao Z. C. (2016 ). p38 MAPK Inhibition Improves Synaptic Plasticity and Memory in Angiotensin II-dependent Hypertensive Mice. Sci. Rep. 6:27600.

    Not in our library10.1038/srep27600

  77. 77.

    Damjanov N. Kauffman R. S. Spencer-Green G. T. (2009 ). Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies. Arthritis Rheum. 60 1232–1241.

    Not in our library10.1002/art.24485

  78. 78.

    Dapper J. D. Crish S. D. Pang I. H. Calkins D. J. (2013 ). Proximal inhibition of p38 MAPK stress signaling prevents distal axonopathy. Neurobiol. Dis. 59 26–37.

    Not in our library10.1016/j.nbd.2013.07.001

  79. 79.

    De Vos K. Severin F. Van Herreweghe F. Vancompernolle K. Goossens V. Hyman A. (2000 ). Tumor necrosis factor induces hyperphosphorylation of kinesin light chain and inhibits kinesin-mediated transport of mitochondria. J. Cell Biol. 149 1207–1214.

    Not in our library10.1083/jcb.149.6.1207

  80. 80.

    Dean J. L. Sully G. Clark A. R. Saklatvala J. (2004 ). The involvement of AU-rich element-binding proteins in p38 mitogen-activated protein kinase pathway-mediated mRNA stabilisation. Cell. Signal. 16 1113–1121.

    Not in our library10.1016/j.cellsig.2004.04.006

  81. 81.

    Deb I. Manhas N. Poddar R. Rajagopal S. Allan A. M. Lombroso P. J. (2013 ). Neuroprotective role of a brain-enriched tyrosine phosphatase, STEP, in focal cerebral ischemia. J. Neurosci. 33 17814–17826.

    Not in our library10.1523/jneurosci.2346-12.2013

  82. 82.

    del Barco Barrantes I. Coya J. M. Maina F. Arthur J. S. Nebreda A. R. (2011 ). Genetic analysis of specific and redundant roles for p38alpha and p38beta MAPKs during mouse development. Proc. Natl. Acad. Sci. U.S.A. 108 12764–12769.

    Not in our library10.1073/pnas.1015013108

  83. 83.

    Dewachter I. Reverse D. Caluwaerts N. Ris L. Kuiperi C. Van den Haute C. (2002 ). Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J. Neurosci. 22 3445–3453.

    Not in our library10.1523/jneurosci.22-09-03445.2002

  84. 84.

    Dewil M. dela Cruz V. F. Van Den Bosch L. Robberecht W. (2007 ). Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1(G93A)-induced motor neuron death. Neurobiol. Dis. 26 332–341.

    Not in our library10.1016/j.nbd.2006.12.023

  85. 85.

    Diskin R. Askari N. Capone R. Engelberg D. Livnah O. (2004 ). Active mutants of the human p38alpha mitogen-activated protein kinase. J. Biol. Chem. 279 47040–47049.

    Not in our library10.1074/jbc.m404595200

  86. 86.

    Dusik V. Senthilan P. R. Mentzel B. Hartlieb H. Wulbeck C. Yoshii T. (2014 ). The MAP kinase p38 is part of Drosophila melanogaster’s circadian clock. PLoS Genet. 10:e1004565.

    Not in our library10.1371/journal.pgen.1004565

  87. 87.

    Eales K. L. Palygin O. O’Loughlin T. Rasooli-Nejad S. Gaestel M. Muller J. (2014 ). The MK2/3 cascade regulates AMPAR trafficking and cognitive flexibility. Nat. Commun. 5:4701.

    Not in our library10.1038/ncomms5701

  88. 88.

    Ehrich J. M. Messinger D. I. Knakal C. R. Kuhar J. R. Schattauer S. S. Bruchas M. R. (2015 ). Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons. J. Neurosci. 35 12917–12931.

    Not in our library10.1523/jneurosci.2444-15.2015

  89. 89.

    Emami H. Vucic E. Subramanian S. Abdelbaky A. Fayad Z. A. Du S. (2015 ). The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: a multicenter FDG-PET trial. Atherosclerosis 240 490–496.

    Not in our library10.1016/j.atherosclerosis.2015.03.039

  90. 90.

    Emerling B. M. Platanias L. C. Black E. Nebreda A. R. Davis R. J. Chandel N. S. (2005 ). Mitochondrial reactive oxygen species activation of p38 mitogen-activated protein kinase is required for hypoxia signaling. Mol. Cell. Biol. 25 4853–4862.

    Not in our library10.1128/mcb.25.12.4853-4862.2005

  91. 91.

    Enslen H. Raingeaud J. Davis R. J. (1998 ). Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J. Biol. Chem. 273 1741–1748.

    Not in our library10.1074/jbc.273.3.1741

  92. 92.

    Fabian M. A. Biggs W. H. III Treiber D. K. Atteridge C. E. Azimioara M. D. Benedetti M. G. (2005 ). A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol. 23 329–336.

    Not in our library10.1038/nbt1068

  93. 93.

    Fang C. Wu B. Le N. T. T. Imberdis T. Mercer R. C. C. Harris D. A. (2018 ). Prions activate a p38 MAPK synaptotoxic signaling pathway. PLoS Pathog. 14:e1007283.

    Not in our library10.1371/journal.ppat.1007283

  94. 94.

    Farooq F. Balabanian S. Liu X. Holcik M. MacKenzie A. (2009 ). p38 Mitogen-activated protein kinase stabilizes SMN mRNA through RNA binding protein HuR. Hum. Mol. Genet. 18 4035–4045.

    Not in our library10.1093/hmg/ddp352

  95. 95.
    Distinct partitioning of ALS associated TDP-43, FUS and SOD1 mutants into cellular inclusions · 2015
    No notice
  96. 96.

    Feijoo C. Campbell D. G. Jakes R. Goedert M. Cuenda A. (2005 ). Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38delta at Thr50 promotes microtubule assembly. J. Cell Sci. 118(Pt 2), 397–408.

    Not in our library10.1242/jcs.01655

  97. 97.

    Ferrer I. Blanco R. Carmona M. Puig B. Barrachina M. Gomez C. (2001 ). Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson’s disease and Dementia with Lewy bodies. J. Neural Transm. 108 1383–1396.

    Not in our library10.1007/s007020100015

  98. 98.

    Fitzsimmons B. L. Zattoni M. Svensson C. I. Steinauer J. Hua X. Y. Yaksh T. L. (2010 ). Role of spinal p38alpha and beta MAPK in inflammatory hyperalgesia and spinal COX-2 expression. Neuroreport 21 313–317.

    Not in our library10.1097/wnr.0b013e32833774bf

  99. 99.

    Foster J. D. Cervinski M. A. Gorentla B. K. Vaughan R. A. (2006 ). Regulation of the dopamine transporter by phosphorylation. Handb. Exp. Pharmacol. 175 197–214.

    Not in our library10.1007/3-540-29784-7_10

  100. 100.

    Fragoso G. Haines J. D. Roberston J. Pedraza L. Mushynski W. E. Almazan G. (2007 ). p38 mitogen-activated protein kinase is required for central nervous system myelination. Glia 55 1531–1541.

    Not in our library10.1002/glia.20567

  101. 101.

    Freshney N. W. Rawlinson L. Guesdon F. Jones E. Cowley S. Hsuan J. (1994 ). Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell 78 1039–1049.

    Not in our library10.1016/0092-8674(94)90278-x

  102. 102.

    Galan-Arriero I. Avila-Martin G. Ferrer-Donato A. Gomez-Soriano J. Piazza S. Taylor J. (2015 ). Early treatment with UR13870, a novel inhibitor of p38alpha mitogenous activated protein kinase, prevents hyperreflexia and anxiety behaviors, in the spared nerve injury model of neuropathic pain. Neurosci. Lett. 604 69–74.

    Not in our library10.1016/j.neulet.2015.07.044

  103. 103.

    Ge B. Gram H. Di Padova F. Huang B. New L. Ulevitch R. J. (2002 ). MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha. Science 295 1291–1294.

    Not in our library10.1126/science.1067289

  104. 104.

    Ghasemlou N. Lopez-Vales R. Lachance C. Thuraisingam T. Gaestel M. Radzioch D. (2010 ). Mitogen-activated protein kinase-activated protein kinase 2 (MK2) contributes to secondary damage after spinal cord injury. J. Neurosci. 30 13750–13759.

    Not in our library10.1523/jneurosci.2998-10.2010

  105. 105.

    Gianfriddo M. Melani A. Turchi D. Giovannini M. G. Pedata F. (2004 ). Adenosine and glutamate extracellular concentrations and mitogen-activated protein kinases in the striatum of Huntington transgenic mice. Selective antagonism of adenosine A2A receptors reduces transmitter outflow. Neurobiol. Dis. 17 77–88.

    Not in our library10.1016/j.nbd.2004.05.008

  106. 106.

    Gibbs K. L. Kalmar B. Rhymes E. R. Fellows A. D. Ahmed M. Whiting P. (2018 ). Inhibiting p38 MAPK alpha rescues axonal retrograde transport defects in a mouse model of ALS. Cell Death Dis. 9:596.

    Not in our library10.1038/s41419-018-0624-8

  107. 107.

    Gibson H. E. Edwards J. G. Page R. S. Van Hook M. J. Kauer J. A. (2008 ). TRPV1 channels mediate long-term depression at synapses on hippocampal interneurons. Neuron 57 746–759.

    Not in our library10.1016/j.neuron.2007.12.027

  108. 108.

    Gills J. J. Castillo S. S. Zhang C. Petukhov P. A. Memmott R. M. Hollingshead M. (2007 ). Phosphatidylinositol ether lipid analogues that inhibit AKT also independently activate the stress kinase, p38alpha, through MKK3/6-independent and -dependent mechanisms. J. Biol. Chem. 282 27020–27029.

    Not in our library10.1074/jbc.m701108200

  109. 109.

    Goebel-Goody S. M. Wilson-Wallis E. D. Royston S. Tagliatela S. M. Naegele J. R. Lombroso P. J. (2012 ). Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model. Genes Brain Behav. 11 586–600.

    Not in our library10.1111/j.1601-183x.2012.00781.x

  110. 110.

    Goedert M. Hasegawa M. Jakes R. Lawler S. Cuenda A. Cohen P. (1997 ). Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. FEBS Lett. 409 57–62.

    Not in our library10.1016/s0014-5793(97)00483-3

  111. 111.

    Goginashvili A. Zhang Z. Erbs E. Spiegelhalter C. Kessler P. Mihlan M. (2015 ). Insulin granules. Insulin secretory granules control autophagy in pancreatic beta cells. Science 347 878–882.

    Not in our library10.1126/science.aaa2628

  112. 112.

    Goldin A. L. (1999 ). Diversity of mammalian voltage-gated sodium channels. Ann. N. Y. Acad. Sci. 868 38–50.

    Not in our library10.1111/j.1749-6632.1999.tb11272.x

  113. 113.

    Gong N. Xiao Q. Zhu B. Zhang C. Y. Wang Y. C. Fan H. (2014 ). Activation of spinal glucagon-like peptide-1 receptors specifically suppresses pain hypersensitivity. J. Neurosci. 34 5322–5334.

    Not in our library10.1523/jneurosci.4703-13.2014

  114. 114.

    Gong X. Ming X. Deng P. Jiang Y. (2010 ). Mechanisms regulating the nuclear translocation of p38 MAP kinase. J. Cell. Biochem. 110 1420–1429.

    Not in our library10.1002/jcb.22675

  115. 115.

    Gonzalez-Teran B. Matesanz N. Nikolic I. Verdugo M. A. Sreeramkumar V. Hernandez-Cosido L. (2016 ). p38gamma and p38delta reprogram liver metabolism by modulating neutrophil infiltration. EMBO J. 35 536–552.

    Not in our library10.15252/embj.201591857

  116. 116.

    Graziane N. M. Polter A. M. Briand L. A. Pierce R. C. Kauer J. A. (2013 ). Kappa opioid receptors regulate stress-induced cocaine seeking and synaptic plasticity. Neuron 77 942–954.

    Not in our library10.1016/j.neuron.2012.12.034

  117. 117.

    Guan Z. Kim J. H. Lomvardas S. Holick K. Xu S. Kandel E. R. (2003 ). p38 MAP kinase mediates both short-term and long-term synaptic depression in aplysia. J. Neurosci. 23 7317–7325.

    Not in our library10.1523/jneurosci.23-19-07317.2003

  118. 118.

    Guldal C. G. Ahmad A. Korshunov A. Squatrito M. Awan A. Mainwaring L. A. (2012 ). An essential role for p38 MAPK in cerebellar granule neuron precursor proliferation. Acta Neuropathol. 123 573–586.

    Not in our library10.1007/s00401-012-0946-z

  119. 119.

    Guo G. Bhat N. R. (2007 ). p38alpha MAP kinase mediates hypoxia-induced motor neuron cell death: a potential target of minocycline’s neuroprotective action. Neurochem. Res. 32 2160–2166.

    Not in our library10.1007/s11064-007-9408-8

  120. 120.

    Guo Y. L. Ye J. Huang F. (2007 ). p38alpha MAP kinase-deficient mouse embryonic stem cells can differentiate to endothelial cells, smooth muscle cells, and neurons. Dev. Dyn. 236 3383–3392.

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    Gupta J. Nebreda A. R. (2015 ). Roles of p38alpha mitogen-activated protein kinase in mouse models of inflammatory diseases and cancer. FEBS J. 282 1841–1857.

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    Haines J. D. Fang J. Mushynski W. E. Almazan G. (2010 ). Mitogen-activated protein kinase activated protein kinase 2 (MK2) participates in p38 MAPK regulated control of oligodendrocyte differentiation. Glia 58 1384–1393.

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    Haines J. D. Fulton D. L. Richard S. Almazan G. (2015 ). p38 Mitogen-Activated Protein Kinase Pathway Regulates Genes during Proliferation and Differentiation in Oligodendrocytes. PLoS One 10:e0145843.

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    Halassa M. M. Fellin T. Haydon P. G. (2007 ). The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol. Med. 13 54–63.

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    Hammad M. Silva A. Glass J. Sladky J. T. Benatar M. (2007 ). Clinical, electrophysiologic, and pathologic evidence for sensory abnormalities in ALS. Neurology 69 2236–2242.

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    Han J. Lee J. D. Bibbs L. Ulevitch R. J. (1994 ). A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265 808–811.

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    Han Q. Q. Huang H. J. Wang Y. L. Yang L. Pilot A. Zhu X. C. (2019 ). Ghrelin exhibited antidepressant and anxiolytic effect via the p38-MAPK signaling pathway in hippocampus. Prog. Neuropsychopharmacol. Biol. Psychiatry 93 11–20.

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    Harada A. Oguchi K. Okabe S. Kuno J. Terada S. Ohshima T. (1994 ). Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 369 488–491.

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    Hardingham G. E. Bading H. (2003 ). The Yin and Yang of NMDA receptor signalling. Trends Neurosci. 26 81–89.

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    Hayashi Y. Sanada K. Hirota T. Shimizu F. Fukada Y. (2003 ). p38 mitogen-activated protein kinase regulates oscillation of chick pineal circadian clock. J. Biol. Chem. 278 25166–25171.

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    He Y. She H. Zhang T. Xu H. Cheng L. Yepes M. (2018 ). p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1. J. Cell Biol. 217 315–328.

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    Heinrichsdorff J. Luedde T. Perdiguero E. Nebreda A. R. Pasparakis M. (2008 ). p38 alpha MAPK inhibits JNK activation and collaborates with IkappaB kinase 2 to prevent endotoxin-induced liver failure. EMBO Rep. 9 1048–1054.

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    Heinsbroek J. A. Furbish A. B. Peters J. (2018 ). A single, extinction-based treatment with a kappa opioid receptor agonist elicits a long-term reduction in cocaine relapse. Neuropsychopharmacology 43 1492–1497.

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    Henley J. M. Wilkinson K. A. (2016 ). Synaptic AMPA receptor composition in development, plasticity and disease. Nat. Rev. Neurosci. 17 337–350.

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    Herlaar E. Brown Z. (1999 ). p38 MAPK signalling cascades in inflammatory disease. Mol. Med. Today 5 439–447.

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    Hideshima T. Podar K. Chauhan D. Ishitsuka K. Mitsiades C. Tai Y. T. (2004 ). p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. Oncogene 23 8766–8776.

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    Hirai S. Cui D. F. Miyata T. Ogawa M. Kiyonari H. Suda Y. (2006 ). The c-Jun N-terminal kinase activator dual leucine zipper kinase regulates axon growth and neuronal migration in the developing cerebral cortex. J. Neurosci. 26 11992–12002.

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    Holasek S. S. Wengenack T. M. Kandimalla K. K. Montano C. Gregor D. M. Curran G. L. (2005 ). Activation of the stress-activated MAP kinase, p38, but not JNK in cortical motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in transgenic mice. Brain Res. 1045 185–198.

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    Hossain S. de la Cruz-Morcillo M. A. Sanchez-Prieto R. Almazan G. (2012 ). Mitogen-activated protein kinase p38 regulates Krox-20 to direct Schwann cell differentiation and peripheral myelination. Glia 60 1130–1144.

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    Hsieh C. C. Kuro-o M. Rosenblatt K. P. Brobey R. Papaconstantinou J. (2010 ). The ASK1-Signalosome regulates p38 MAPK activity in response to levels of endogenous oxidative stress in the Klotho mouse models of aging. Aging 2 597–611.

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    Hsieh H. Boehm J. Sato C. Iwatsubo T. Tomita T. Sisodia S. (2006 ). AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52 831–843.

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    Huang C. C. You J. L. Wu M. Y. Hsu K. S. (2004 ). Rap1-induced p38 mitogen-activated protein kinase activation facilitates AMPA receptor trafficking via the GDI.Rab5 complex. Potential role in (S)-3,5-dihydroxyphenylglycene-induced long term depression. J. Biol. Chem. 279 12286–12292.

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    Huang Q. Mao X. F. Wu H. Y. Liu H. Sun M. L. Wang X. (2017 ). Cynandione A attenuates neuropathic pain through p38beta MAPK-mediated spinal microglial expression of beta-endorphin. Brain Behav. Immun. 62 64–77.

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    Hudmon A. Choi J. S. Tyrrell L. Black J. A. Rush A. M. Waxman S. G. (2008 ). Phosphorylation of sodium channel Na(v)1.8 by p38 mitogen-activated protein kinase increases current density in dorsal root ganglion neurons. J. Neurosci. 28 3190–3201.

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    Huganir R. L. Nicoll R. A. (2013 ). AMPARs and synaptic plasticity: the last 25 years. Neuron 80 704–717.

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    Hui L. Bakiri L. Mairhorfer A. Schweifer N. Haslinger C. Kenner L. (2007 ). p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat. Genet. 39 741–749.

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    Hynes N. E. Ingham P. W. Lim W. A. Marshall C. J. Massague J. Pawson T. (2013 ). Signalling change: signal transduction through the decades. Nat. Rev. Mol. Cell Biol. 14 393–398.

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    Ittner A. Asih P. R. Tan A. R. P. Prikas E. Bertz J. Stefanoska K. (2020 ). Reduction of advanced tau-mediated memory deficits by the MAP kinase p38gamma. Acta Neuropathol. 140 279–294.

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    Ittner A. Block H. Reichel C. A. Varjosalo M. Gehart H. Sumara G. (2012 ). Regulation of PTEN activity by p38delta-PKD1 signaling in neutrophils confers inflammatory responses in the lung. J. Exp. Med. 209 2229–2246.

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    Ittner A. Chua S. W. Bertz J. Volkerling A. van der Hoven J. Gladbach A. (2016 ). Site-specific phosphorylation of tau inhibits amyloid-beta toxicity in Alzheimer’s mice. Science 354 904–908.

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    Ittner A. Ittner L. M. (2018 ). Dendritic Tau in Alzheimer’s Disease. Neuron 99 13–27.

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    Ittner A. A. Gladbach A. Bertz J. Suh L. S. Ittner L. M. (2014 ). p38 MAP kinase-mediated NMDA receptor-dependent suppression of hippocampal hypersynchronicity in a mouse model of Alzheimer’s disease. Acta Neuropathol. Commun. 2:149.

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    Ittner L. M. Gotz J. (2011 ). Amyloid-beta and tau–a toxic pas de deux in Alzheimer’s disease. Nat. Rev. Neurosci. 12 65–72.

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    Ittner L. M. Ke Y. D. Delerue F. Bi M. Gladbach A. van Eersel J. (2010 ). Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142 387–397.

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    Jackson J. R. Bolognese B. Hillegass L. Kassis S. Adams J. Griswold D. E. (1998 ). Pharmacological effects of SB 220025, a selective inhibitor of P38 mitogen-activated protein kinase, in angiogenesis and chronic inflammatory disease models. J. Pharmacol. Exp. Ther. 284 687–692.

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    Jan A. T. Malik M. A. Rahman S. Yeo H. R. Lee E. J. Abdullah T. S. (2017 ). Perspective insights of exosomes in neurodegenerative diseases: a critical appraisal. Front. Aging Neurosci. 9:317.

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    Jeffrey K. L. Camps M. Rommel C. Mackay C. R. (2007 ). Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses. Nat. Rev. Drug Discov. 6 391–403.

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    Jeohn G. H. Cooper C. L. Wilson B. Chang R. C. Jang K. J. Kim H. C. (2002 ). p38 MAP kinase is involved in lipopolysaccharide-induced dopaminergic neuronal cell death in rat mesencephalic neuron-glia cultures. Ann. N. Y. Acad. Sci. 962 332–346.

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    Ji R. R. Samad T. A. Jin S. X. Schmoll R. Woolf C. J. (2002 ). p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36 57–68.

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    Jiang Y. Gram H. Zhao M. New L. Gu J. Feng L. (1997 ). Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta. J. Biol. Chem. 272 30122–30128.

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    Jin M. Shepardson N. Yang T. Chen G. Walsh D. Selkoe D. J. (2011 ). Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc. Natl. Acad. Sci. U.S.A. 108 5819–5824.

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    Karitzky J. Ludolph A. C. (2001 ). Imaging and neurochemical markers for diagnosis and disease progression in ALS. J. Neurol. Sci. 191 35–41.

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    Karunakaran S. Saeed U. Mishra M. Valli R. K. Joshi S. D. Meka D. P. (2008 ). Selective activation of p38 mitogen-activated protein kinase in dopaminergic neurons of substantia nigra leads to nuclear translocation of p53 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice. J. Neurosci. 28 12500–12509.

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    Kase Y. Otsu K. Shimazaki T. Okano H. (2019 ). Involvement of p38 in Age-Related Decline in Adult Neurogenesis via Modulation of Wnt Signaling. Stem Cell Rep. 12 1313–1328.

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    Kasuya Y. Umezawa H. Hatano M. (2018 ). Stress-Activated Protein Kinases in Spinal Cord Injury: Focus on Roles of p38. Int. J. Mol. Sci. 19:867.

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    Kato Y. Chao T. H. Hayashi M. Tapping R. I. Lee J. D. (2000 ). Role of BMK1 in regulation of growth factor-induced cellular responses. Immunol. Res. 21 233–237.

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    Kawasaki H. Morooka T. Shimohama S. Kimura J. Hirano T. Gotoh Y. (1997 ). Activation and involvement of p38 mitogen-activated protein kinase in glutamate-induced apoptosis in rat cerebellar granule cells. J. Biol. Chem. 272 18518–18521.

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    Kelkar N. Standen C. L. Davis R. J. (2005 ). Role of the JIP4 scaffold protein in the regulation of mitogen-activated protein kinase signaling pathways. Mol. Cell. Biol. 25 2733–2743.

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    Kim C. Sano Y. Todorova K. Carlson B. A. Arpa L. Celada A. (2008 ). The kinase p38 alpha serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression. Nat. Immunol. 9 1019–1027.

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    Kimura Y. Tsutsumi K. Konno A. Ikegami K. Hameed S. Kaneko T. (2018 ). Environmental responsiveness of tubulin glutamylation in sensory cilia is regulated by the p38 MAPK pathway. Sci. Rep. 8:8392.

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    Kirby L. G. Zeeb F. D. Winstanley C. A. (2011 ). Contributions of serotonin in addiction vulnerability. Neuropharmacology 61 421–432.

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    Klinedinst S. Wang X. Xiong X. Haenfler J. M. Collins C. A. (2013 ). Independent pathways downstream of the Wnd/DLK MAPKKK regulate synaptic structure, axonal transport, and injury signaling. J. Neurosci. 33 12764–12778.

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    Kosakai A. Ito D. Nihei Y. Yamashita S. Okada Y. Takahashi K. (2011 ). Degeneration of mesencephalic dopaminergic neurons in klotho mouse related to vitamin D exposure. Brain Res. 1382 109–117.

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    Kotlyarov A. Yannoni Y. Fritz S. Laass K. Telliez J. B. Pitman D. (2002 ). Distinct cellular functions of MK2. Mol. Cell. Biol. 22 4827–4835.

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    Krapivinsky G. Medina I. Krapivinsky L. Gapon S. Clapham D. E. (2004 ). SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation. Neuron 43 563–574.

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    Krieger C. Hu J. H. Pelech S. (2003 ). Aberrant protein kinases and phosphoproteins in amyotrophic lateral sclerosis. Trends Pharmacol. Sci. 24 535–541.

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    Kuma Y. Campbell D. G. Cuenda A. (2004 ). Identification of glycogen synthase as a new substrate for stress-activated protein kinase 2b/p38beta. Biochem. J. 379(Pt 1), 133–139.

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    Kyriakis J. M. Avruch J. (2001 ). Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 81 807–869.

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    Lawson S. K. Dobrikova E. Y. Shveygert M. Gromeier M. (2013 ). p38alpha mitogen-activated protein kinase depletion and repression of signal transduction to translation machinery by miR-124 and -128 in neurons. Mol. Cell. Biol. 33 127–135.

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    Lee J. Shin J. S. Park J. Y. Kwon D. Choi S. J. Kim S. J. (2003 ). p38 mitogen-activated protein kinase modulates expression of tumor necrosis factor-related apoptosis-inducing ligand induced by interferon-gamma in fetal brain astrocytes. J. Neurosci. Res. 74 884–890.

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    Lee J. C. Laydon J. T. McDonnell P. C. Gallagher T. F. Kumar S. Green D. (1994 ). A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372 739–746.

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    Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease · 2017
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    Lee J. K. Shin J. H. Hwang S. G. Gwag B. J. McKee A. C. Lee J. (2013 ). MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS. Proc. Natl. Acad. Sci. U.S.A. 110 12066–12071.

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    Lee S. H. Park J. Che Y. Han P. L. Lee J. K. (2000 ). Constitutive activity and differential localization of p38alpha and p38beta MAPKs in adult mouse brain. J. Neurosci. Res. 60 623–631.

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  186. 186.

    Lee Y. B. Schrader J. W. Kim S. U. (2000 ). p38 map kinase regulates TNF-alpha production in human astrocytes and microglia by multiple mechanisms. Cytokine 12 874–880.

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    Legos J. J. Erhardt J. A. White R. F. Lenhard S. C. Chandra S. Parsons A. A. (2001 ). SB 239063, a novel p38 inhibitor, attenuates early neuronal injury following ischemia. Brain Res. 892 70–77.

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  188. 188.

    Lemos J. C. Roth C. A. Messinger D. I. Gill H. K. Phillips P. E. Chavkin C. (2012 ). Repeated stress dysregulates kappa-opioid receptor signaling in the dorsal raphe through a p38alpha MAPK-dependent mechanism. J. Neurosci. 32 12325–12336.

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  189. 189.

    Li L. L. Ginet V. Liu X. Vergun O. Tuittila M. Mathieu M. (2013 ). The nNOS-p38MAPK pathway is mediated by NOS1AP during neuronal death. J. Neurosci. 33 8185–8201.

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    Li M. Liu J. Zhang C. (2011 ). Evolutionary history of the vertebrate mitogen activated protein kinases family. PLoS One 6:e26999.

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    Li S. Jin M. Koeglsperger T. Shepardson N. E. Shankar G. M. Selkoe D. J. (2011 ). Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J. Neurosci. 31 6627–6638.

    Not in our library10.1523/jneurosci.0203-11.2011

  192. 192.

    Li S. Tian X. Hartley D. M. Feig L. A. (2006 ). Distinct roles for Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 in the induction of long-term potentiation and long-term depression. J. Neurosci. 26 1721–1729.

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  193. 193.

    Lo U. Selvaraj V. Plane J. M. Chechneva O. V. Otsu K. Deng W. (2014 ). p38alpha (MAPK14) critically regulates the immunological response and the production of specific cytokines and chemokines in astrocytes. Sci. Rep. 4:7405.

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  194. 194.

    Loy B. Apostolova G. Dorn R. McGuire V. A. Arthur J. S. Dechant G. (2011 ). p38alpha and p38beta mitogen-activated protein kinases determine cholinergic transdifferentiation of sympathetic neurons. J. Neurosci. 31 12059–12067.

    Not in our library10.1523/jneurosci.0448-11.2011

  195. 195.

    Lu Q. Rau T. F. Harris V. Johnson M. Poulsen D. J. Black S. M. (2011 ). Increased p38 mitogen-activated protein kinase signaling is involved in the oxidative stress associated with oxygen and glucose deprivation in neonatal hippocampal slice cultures. Eur. J. Neurosci. 34 1093–1101.

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  196. 196.

    Maillet A. Krack P. Lhommee E. Metereau E. Klinger H. Favre E. (2016 ). The prominent role of serotonergic degeneration in apathy, anxiety and depression in de novo Parkinson’s disease. Brain 139(Pt 9), 2486–2502.

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    Mannangatti P. NarasimhaNaidu K. Damaj M. I. Ramamoorthy S. Jayanthi L. D. (2015 ). A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference. J. Biol. Chem. 290 10814–10827.

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  198. 198.

    Maphis N. Jiang S. Xu G. Kokiko-Cochran O. N. Roy S. M. Van Eldik L. J. (2016 ). Selective suppression of the alpha isoform of p38 MAPK rescues late-stage tau pathology. Alzheimers Res. Ther. 8:54.

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    Menon M. B. Dhamija S. Kotlyarov A. Gaestel M. (2015 ). The problem of pyridinyl imidazole class inhibitors of MAPK14/p38alpha and MAPK11/p38beta in autophagy research. Autophagy 11 1425–1427.

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  200. 200.

    Mittelstadt P. R. Salvador J. M. Fornace A. J. Jr. Ashwell J. D. (2005 ). Activating p38 MAPK: new tricks for an old kinase. Cell Cycle 4 1189–1192.

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    Mizumura K. Takeda K. Hashimoto S. Horie T. Ichijo H. (2006 ). Identification of Op18/stathmin as a potential target of ASK1-p38 MAP kinase cascade. J. Cell. Physiol. 206 363–370.

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    Morfini G. A. Bosco D. A. Brown H. Gatto R. Kaminska A. Song Y. (2013 ). Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. PLoS One 8:e65235.

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    Morganti J. M. Goulding D. S. Van Eldik L. J. (2019 ). Deletion of p38alpha MAPK in microglia blunts trauma-induced inflammatory responses in mice. J. Neuroinflam. 16:98.

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    Mori T. Wang X. Jung J. C. Sumii T. Singhal A. B. Fini M. E. (2002 ). Mitogen-activated protein kinase inhibition in traumatic brain injury: in vitro and in vivo effects. J. Cereb. Blood Flow Metab. 22 444–452.

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    Morrison D. K. (2012 ). MAP kinase pathways. Cold Spring Harb. Perspect. Biol. 4:a011254.

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    Moult P. R. Correa S. A. Collingridge G. L. Fitzjohn S. M. Bashir Z. I. (2008 ). Co-activation of p38 mitogen-activated protein kinase and protein tyrosine phosphatase underlies metabotropic glutamate receptor-dependent long-term depression. J. Physiol. 586 2499–2510.

    Not in our library10.1113/jphysiol.2008.153122

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    Mucke L. Selkoe D. J. (2012 ). Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harb. Perspect. Med. 2:a006338.

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  208. 208.

    Muda M. Theodosiou A. Rodrigues N. Boschert U. Camps M. Gillieron C. (1996 ). The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases. J. Biol. Chem. 271 27205–27208.

    Not in our library10.1074/jbc.271.44.27205

  209. 209.

    Munoz J. J. Tarrega C. Blanco-Aparicio C. Pulido R. (2003 ). Differential interaction of the tyrosine phosphatases PTP-SL, STEP and HePTP with the mitogen-activated protein kinases ERK1/2 and p38alpha is determined by a kinase specificity sequence and influenced by reducing agents. Biochem. J. 372(Pt 1), 193–201.

    Not in our library10.1042/bj20021941

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    Munoz L. Ammit A. J. (2010 ). Targeting p38 MAPK pathway for the treatment of Alzheimer’s disease. Neuropharmacology 58 561–568.

    Not in our library10.1016/j.neuropharm.2009.11.010

  211. 211.

    Murray H. J. O’Connor J. J. (2003 ). A role for COX-2 and p38 mitogen activated protein kinase in long-term depression in the rat dentate gyrus in vitro. Neuropharmacology 44 374–380.

    Not in our library10.1016/s0028-3908(02)00375-1

  212. 212.

    Nabavi S. Fox R. Alfonso S. Aow J. Malinow R. (2014 ). GluA1 trafficking and metabotropic NMDA: addressing results from other laboratories inconsistent with ours. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369 20130145.

    Not in our library10.1098/rstb.2013.0145

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    Nabavi S. Kessels H. W. Alfonso S. Aow J. Fox R. Malinow R. (2013 ). Metabotropic NMDA receptor function is required for NMDA receptor-dependent long-term depression. Proc. Natl. Acad. Sci. U.S.A. 110 4027–4032.

    Not in our library10.1073/pnas.1219454110

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    Nahirnyj A. Livne-Bar I. Guo X. Sivak J. M. (2013 ). ROS detoxification and proinflammatory cytokines are linked by p38 MAPK signaling in a model of mature astrocyte activation. PLoS One 8:e83049.

    Not in our library10.1371/journal.pone.0083049

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    Nakata K. Abrams B. Grill B. Goncharov A. Huang X. Chisholm A. D. (2005 ). Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development. Cell 120 407–420.

    Not in our library10.1016/j.cell.2004.12.017

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    Namiki K. Nakamura A. Furuya M. Mizuhashi S. Matsuo Y. Tokuhara N. (2007 ). Involvement of p38alpha in kainate-induced seizure and neuronal cell damage. J. Recept. Signal Transduct. Res. 27 99–111.

    Not in our library10.1080/10799890701357855

  217. 217.

    Nemoto S. Xiang J. Huang S. Lin A. (1998 ). Induction of apoptosis by SB202190 through inhibition of p38beta mitogen-activated protein kinase. J. Biol. Chem. 273 16415–16420.

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    Nito C. Kamada H. Endo H. Niizuma K. Myer D. J. Chan P. H. (2008 ). Role of the p38 mitogen-activated protein kinase/cytosolic phospholipase A2 signaling pathway in blood-brain barrier disruption after focal cerebral ischemia and reperfusion. J. Cereb. Blood Flow Metab. 28 1686–1696.

    Not in our library10.1038/jcbfm.2008.60

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    Nix P. Hisamoto N. Matsumoto K. Bastiani M. (2011 ). Axon regeneration requires coordinate activation of p38 and JNK MAPK pathways. Proc. Natl. Acad. Sci. U.S.A. 108 10738–10743.

    Not in our library10.1073/pnas.1104830108

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    Noseda R. Guerrero-Valero M. Alberizzi V. Previtali S. C. Sherman D. L. Palmisano M. (2016 ). Kif13b Regulates PNS and CNS Myelination through the Dlg1 Scaffold. PLoS Biol. 14:e1002440.

    Not in our library10.1371/journal.pbio.1002440

  221. 221.
    Antiapoptotic role of the p38 mitogen-activated protein kinase–myocyte enhancer factor 2 transcription factor pathway during neuronal differentiation · 2000
    Not checked
  222. 222.

    Origlia N. Righi M. Capsoni S. Cattaneo A. Fang F. Stern D. M. (2008 ). Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-beta-mediated cortical synaptic dysfunction. J. Neurosci. 28 3521–3530.

    Not in our library10.1523/jneurosci.0204-08.2008

  223. 223.

    Park E. C. Rongo C. (2016 ). The p38 MAP kinase pathway modulates the hypoxia response and glutamate receptor trafficking in aging neurons. eLife 5:e12010.

    Not in our library10.7554/elife.12010

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    Parker C. G. Hunt J. Diener K. McGinley M. Soriano B. Keesler G. A. (1998 ). Identification of stathmin as a novel substrate for p38 delta. Biochem. Biophys. Res. Commun. 249 791–796.

    Not in our library10.1006/bbrc.1998.9250

  225. 225.

    Patterson K. I. Brummer T. O’Brien P. M. Daly R. J. (2009 ). Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem. J. 418 475–489.

    Not in our library10.1042/bj20082234

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    Piao C. S. Che Y. Han P. L. Lee J. K. (2002 ). Delayed and differential induction of p38 MAPK isoforms in microglia and astrocytes in the brain after transient global ischemia. Brain Res. Mol. Brain Res. 107 137–144.

    Not in our library10.1016/s0169-328x(02)00456-4

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    Piao C. S. Kim J. B. Han P. L. Lee J. K. (2003 ). Administration of the p38 MAPK inhibitor SB203580 affords brain protection with a wide therapeutic window against focal ischemic insult. J. Neurosci. Res. 73 537–544.

    Not in our library10.1002/jnr.10671

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    Poddar R. Deb I. Mukherjee S. Paul S. (2010 ). NR2B-NMDA receptor mediated modulation of the tyrosine phosphatase STEP regulates glutamate induced neuronal cell death. J. Neurochem. 115 1350–1362.

    Not in our library10.1111/j.1471-4159.2010.07035.x

  229. 229.
    p38γ Mitogen-Activated Protein Kinase Is a Key Regulator in Skeletal Muscle Metabolic Adaptation in Mice · 2009
    No notice
  230. 230.

    Politis M. Niccolini F. (2015 ). Serotonin in Parkinson’s disease. Behav. Brain Res. 277 136–145.

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    Potolicchio I. Carven G. J. Xu X. Stipp C. Riese R. J. Stern L. J. (2005 ). Proteomic analysis of microglia-derived exosomes: metabolic role of the aminopeptidase CD13 in neuropeptide catabolism. J. Immunol. 175 2237–2243.

    Not in our library10.4049/jimmunol.175.4.2237

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    Pozniak C. D. Sengupta Ghosh A. Gogineni A. Hanson J. E. Lee S. H. Larson J. L. (2013 ). Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration. J. Exp. Med. 210 2553–2567.

    Not in our library10.1084/jem.20122832

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    Prikas E. Poljak A. Ittner A. (2020 ). Mapping p38alpha mitogen-activated protein kinase signaling by proximity-dependent labeling. Protein Sci. 29 1196–1210.

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    Pulido R. Zuniga A. Ullrich A. (1998 ). PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif. EMBO J. 17 7337–7350.

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    Raingeaud J. Gupta S. Rogers J. S. Dickens M. Han J. Ulevitch R. J. (1995 ). Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J. Biol. Chem. 270 7420–7426.

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    Rangone H. Poizat G. Troncoso J. Ross C. A. MacDonald M. E. Saudou F. (2004 ). The serum- and glucocorticoid-induced kinase SGK inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin. Eur. J. Neurosci. 19 273–279.

    Not in our library10.1111/j.0953-816x.2003.03131.x

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    Ray A. Sehgal N. Karunakaran S. Rangarajan G. Ravindranath V. (2015 ). MPTP activates ASK1-p38 MAPK signaling pathway through TNF-dependent Trx1 oxidation in parkinsonism mouse model. Free Radic. Biol. Med. 87 312–325.

    Not in our library10.1016/j.freeradbiomed.2015.06.041

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    Reed-Geaghan E. G. Savage J. C. Hise A. G. Landreth G. E. (2009 ). CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J. Neurosci. 29 11982–11992.

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    Regan J. Capolino A. Cirillo P. F. Gilmore T. Graham A. G. Hickey E. (2003 ). Structure-activity relationships of the p38alpha MAP kinase inhibitor 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796). J. Med. Chem. 46 4676–4686.

    Not in our library10.1021/jm030121k

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    Ren J. Zhang S. Kovacs A. Wang Y. Muslin A. J. (2005 ). Role of p38alpha MAPK in cardiac apoptosis and remodeling after myocardial infarction. J. Mol. Cell Cardiol. 38 617–623.

    Not in our library10.1016/j.yjmcc.2005.01.012

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    Risco A. del Fresno C. Mambol A. Alsina-Beauchamp D. MacKenzie K. F. Yang H. T. (2012 ). p38gamma and p38delta kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation. Proc. Natl. Acad. Sci. U.S.A. 109 11200–11205.

    Not in our library10.1073/pnas.1207290109

  242. 242.

    Roberson E. D. Scearce-Levie K. Palop J. J. Yan F. Cheng I. H. Wu T. (2007 ). Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316 750–754.

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    Roberts S. L. Dun X. P. Dee G. Gray B. Mindos T. Parkinson D. B. (2017 ). The role of p38alpha in Schwann cells in regulating peripheral nerve myelination and repair. J. Neurochem. 141 37–47.

    Not in our library10.1111/jnc.13929

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    Robson M. J. Quinlan M. A. Margolis K. G. Gajewski-Kurdziel P. A. Veenstra-VanderWeele J. Gershon M. D. (2018 ). p38alpha MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse. Proc. Natl. Acad. Sci. U.S.A. 115 E10245–E10254.

    Not in our library10.1073/pnas.1809137115

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    Roccaro A. M. Ghobrial I. M. Blotta S. Treon S. P. Malagola M. Anderson K. C. (2008 ). Advances in the treatment of monoclonal gammopaties: the emerging role of targeted therapy in plasma cell dyscrasias. Biologics 2 419–431.

    Not in our library10.2147/btt.s3088

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    Rohm S. Berger B. T. Schroder M. Chaikuad A. Winkel R. Hekking K. F. W. (2019 ). Fast Iterative Synthetic Approach toward Identification of Novel Highly Selective p38 MAP Kinase Inhibitors. J. Med. Chem. 62 10757–10782.

    Not in our library10.1021/acs.jmedchem.9b01227

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    Rouse J. Cohen P. Trigon S. Morange M. Alonso-Llamazares A. Zamanillo D. (1994 ). A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 78 1027–1037.

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    Roy Choudhury G. Ryou M. G. Poteet E. Wen Y. He R. Sun F. (2014 ). Involvement of p38 MAPK in reactive astrogliosis induced by ischemic stroke. Brain Res. 1551 45–58.

    Not in our library10.1016/j.brainres.2014.01.013

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    Rumbaugh G. Adams J. P. Kim J. H. Huganir R. L. (2006 ). SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Proc. Natl. Acad. Sci. U.S.A. 103 4344–4351.

    Not in our library10.1073/pnas.0600084103

  250. 250.

    Rush A. M. Wu J. Rowan M. J. Anwyl R. (2002 ). Group I metabotropic glutamate receptor (mGluR)-dependent long-term depression mediated via p38 mitogen-activated protein kinase is inhibited by previous high-frequency stimulation and activation of mGluRs and protein kinase C in the rat dentate gyrus in vitro. J. Neurosci. 22 6121–6128.

    Not in our library10.1523/jneurosci.22-14-06121.2002

  251. 251.

    Sabio G. Arthur J. S. Kuma Y. Peggie M. Carr J. Murray-Tait V. (2005 ). p38gamma regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP. EMBO J. 24 1134–1145.

    Not in our library10.1038/sj.emboj.7600578

  252. 252.

    Salvador J. M. Mittelstadt P. R. Guszczynski T. Copeland T. D. Yamaguchi H. Appella E. (2005 ). Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases. Nat. Immunol. 6 390–395.

    Not in our library10.1038/ni1177

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    Sama R. R. Fallini C. Gatto R. McKeon J. E. Song Y. Rotunno M. S. (2017 ). ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation. Sci. Rep. 7:115.

    Not in our library10.1038/s41598-017-00091-1

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    Sanchez A. Tripathy D. Yin X. Desobry K. Martinez J. Riley J. (2012 ). p38 MAPK: a mediator of hypoxia-induced cerebrovascular inflammation. J. Alzheimers. Dis. 32 587–597.

    Not in our library10.3233/jad-2012-120829

  255. 255.

    Santello M. Cali C. Bezzi P. (2012 ). Gliotransmission and the tripartite synapse. Adv. Exp. Med. Biol. 970 307–331.

    Not in our library10.1007/978-3-7091-0932-8_14

  256. 256.

    Sau D. De Biasi S. Vitellaro-Zuccarello L. Riso P. Guarnieri S. Porrini M. (2007 ). Mutation of SOD1 in ALS: a gain of a loss of function. Hum. Mol. Genet. 16 1604–1618.

    Not in our library10.1093/hmg/ddm110

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    Scherzinger E. Lurz R. Turmaine M. Mangiarini L. Hollenbach B. Hasenbank R. (1997 ). Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 90 549–558.

    Not in our library10.1016/s0092-8674(00)80514-0

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    Schindlbeck K. A. Eidelberg D. (2018 ). Network imaging biomarkers: insights and clinical applications in Parkinson’s disease. Lancet Neurol. 17 629–640.

    Not in our library10.1016/s1474-4422(18)30169-8

  259. 259.

    Schindler A. G. Messinger D. I. Smith J. S. Shankar H. Gustin R. M. Schattauer S. S. (2012 ). Stress produces aversion and potentiates cocaine reward by releasing endogenous dynorphins in the ventral striatum to locally stimulate serotonin reuptake. J. Neurosci. 32 17582–17596.

    Not in our library10.1523/jneurosci.3220-12.2012

  260. 260.

    Schnoder L. Hao W. Qin Y. Liu S. Tomic I. Liu X. (2016 ). Deficiency of Neuronal p38alpha MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1. J. Biol. Chem. 291 2067–2079.

    Not in our library10.1074/jbc.m115.695916

  261. 261.

    Schreiber S. Feagan B. D’Haens G. Colombel J. F. Geboes K. Yurcov M. (2006 ). Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Clin. Gastroenterol. Hepatol. 4, 325–334.

    Not in our library10.1016/j.cgh.2005.11.013

  262. 262.

    Scior T. Domeyer D. M. Cuanalo-Contreras K. Laufer S. A. (2011 ). Pharmacophore design of p38alpha MAP kinase inhibitors with either 2,4,5-trisubstituted or 1,2,4,5-tetrasubstituted imidazole scaffold. Curr. Med. Chem. 18 1526–1539.

    Not in our library10.2174/092986711795328409

  263. 263.

    Segarra J. Balenci L. Drenth T. Maina F. Lamballe F. (2006 ). Combined signaling through ERK, PI3K/AKT, and RAC1/p38 is required for met-triggered cortical neuron migration. J. Biol. Chem. 281 4771–4778.

    Not in our library10.1074/jbc.m508298200

  264. 264.

    Semenova M. M. Maki-Hokkonen A. M. Cao J. Komarovski V. Forsberg K. M. Koistinaho M. (2007 ). Rho mediates calcium-dependent activation of p38alpha and subsequent excitotoxic cell death. Nat. Neurosci. 10 436–443.

    Not in our library10.1038/nn1869

  265. 265.

    Shanware N. P. Williams L. M. Bowler M. J. Tibbetts R. S. (2009 ). Non-specific in vivo inhibition of CK1 by the pyridinyl imidazole p38 inhibitors SB 203580 and SB 202190. BMB Rep. 42 142–147.

    Not in our library10.5483/bmbrep.2009.42.3.142

  266. 266.

    Shi G. X. Han J. Andres D. A. (2005 ). Rin GTPase couples nerve growth factor signaling to p38 and b-Raf/ERK pathways to promote neuronal differentiation. J. Biol. Chem. 280 37599–37609.

    Not in our library10.1074/jbc.m507364200

  267. 267.
    Post-ischemic inflammation regulates neural damage and protection · 2014
    No notice
  268. 268.

    Shin J. H. Jeong J. Y. Jin Y. Kim I. D. Lee J. K. (2011 ). p38beta MAPK affords cytoprotection against oxidative stress-induced astrocyte apoptosis via induction of alphaB-crystallin and its anti-apoptotic function. Neurosci. Lett. 501 132–137.

    Not in our library10.1016/j.neulet.2011.06.061

  269. 269.

    Sirabella R. Secondo A. Pannaccione A. Molinaro P. Formisano L. Guida N. (2012 ). ERK1/2, p38, and JNK regulate the expression and the activity of the three isoforms of the Na+/Ca2+ exchanger, NCX1, NCX2, and NCX3, in neuronal PC12 cells. J. Neurochem. 122 911–922.

    Not in our library10.1111/j.1471-4159.2012.07838.x

  270. 270.

    Song Y. Nagy M. Ni W. Tyagi N. K. Fenton W. A. Lopez-Giraldez F. (2013 ). Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm. Proc. Natl. Acad. Sci. U.S.A. 110 5428–5433.

    Not in our library10.1073/pnas.1303279110

  271. 271.

    Soriano F. X. Martel M. A. Papadia S. Vaslin A. Baxter P. Rickman C. (2008 ). Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand. J. Neurosci. 28 10696–10710.

    Not in our library10.1523/jneurosci.1207-08.2008

  272. 272.

    Stamboulian S. Choi J. S. Ahn H. S. Chang Y. W. Tyrrell L. Black J. A. (2010 ). ERK1/2 mitogen-activated protein kinase phosphorylates sodium channel Na(v)1.7 and alters its gating properties. J. Neurosci. 30 1637–1647.

    Not in our library10.1523/jneurosci.4872-09.2010

  273. 273.

    Stefanoska K. Bertz J. Volkerling A. M. van der Hoven J. Ittner L. M. Ittner A. (2018 ). Neuronal MAP kinase p38alpha inhibits c-Jun N-terminal kinase to modulate anxiety-related behaviour. Sci. Rep. 8:14296.

    Not in our library10.1038/s41598-018-32592-y

  274. 274.

    Stein I. S. Gray J. A. Zito K. (2015 ). Non-Ionotropic NMDA Receptor Signaling Drives Activity-Induced Dendritic Spine Shrinkage. J. Neurosci. 35 12303–12308.

    Not in our library10.1523/jneurosci.4289-14.2015

  275. 275.

    Stein I. S. Park D. K. Flores J. C. Jahncke J. N. Zito K. (2020 ). Molecular Mechanisms of Non-ionotropic NMDA Receptor Signaling in Dendritic Spine Shrinkage. J Neurosci. 40:JN-RM-0046-20.

    Not in our library10.1523/jneurosci.0046-20.2020

  276. 276.

    Steinkellner T. Montgomery T. R. Hofmaier T. Kudlacek O. Yang J. W. Rickhag M. (2015 ). Amphetamine action at the cocaine- and antidepressant-sensitive serotonin transporter is modulated by alphaCaMKII. J. Neurosci. 35 8258–8271.

    Not in our library10.1523/jneurosci.4034-14.2015

  277. 277.

    Su P. Zhang J. Wang D. Zhao F. Cao Z. Aschner M. (2016 ). The role of autophagy in modulation of neuroinflammation in microglia. Neuroscience 319 155–167.

    Not in our library10.1016/j.neuroscience.2016.01.035

  278. 278.
    Regulation of PKD by the MAPK p38δ in Insulin Secretion and Glucose Homeostasis · 2009
    No notice
  279. 279.

    Sun A. Liu M. Nguyen X. V. Bing G. (2003 ). P38 MAP kinase is activated at early stages in Alzheimer’s disease brain. Exp. Neurol. 183 394–405.

    Not in our library10.1016/s0014-4886(03)00180-8

  280. 280.

    Svensson C. I. Fitzsimmons B. Azizi S. Powell H. C. Hua X. Y. Yaksh T. L. (2005 ). Spinal p38beta isoform mediates tissue injury-induced hyperalgesia and spinal sensitization. J. Neurochem. 92 1508–1520.

    Not in our library10.1111/j.1471-4159.2004.02996.x

  281. 281.

    Svensson C. I. Marsala M. Westerlund A. Calcutt N. A. Campana W. M. Freshwater J. D. (2003 ). Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J. Neurochem. 86 1534–1544.

    Not in our library10.1046/j.1471-4159.2003.01969.x

  282. 282.

    Swaroop S. Sengupta N. Suryawanshi A. R. Adlakha Y. K. Basu A. (2016 ). HSP60 plays a regulatory role in IL-1beta-induced microglial inflammation via TLR4-p38 MAPK axis. J. Neuroinflam. 13:27.

    Not in our library10.1186/s12974-016-0486-x

  283. 283.

    Sweitzer S. M. Wong S. M. Tjolsen A. Allen C. P. Mochly-Rosen D. Kendig J. J. (2004 ). Exaggerated nociceptive responses on morphine withdrawal: roles of protein kinase C epsilon and gamma. Pain 110 281–289.

    Not in our library10.1016/j.pain.2004.04.004

  284. 284.

    Tai C. Y. Mysore S. P. Chiu C. Schuman E. M. (2007 ). Activity-regulated N-cadherin endocytosis. Neuron 54 771–785.

    Not in our library10.1016/j.neuron.2007.05.013

  285. 285.

    Takahashi Y. Maki T. Liang A. C. Itoh K. Lok J. Osumi N. (2014 ). p38 MAP kinase mediates transforming-growth factor-beta1-induced upregulation of matrix metalloproteinase-9 but not -2 in human brain pericytes. Brain Res. 1593 1–8.

    Not in our library10.1016/j.brainres.2014.10.029

  286. 286.

    Tannenbaum C. S. Koerner T. J. Jansen M. M. Hamilton T. A. (1988 ). Characterization of lipopolysaccharide-induced macrophage gene expression. J. Immunol. 140 3640–3645.

    Not in our library

  287. 287.

    Taylor D. M. Moser R. Regulier E. Breuillaud L. Dixon M. Beesen A. A. (2013 ). MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington’s disease via additive effects of JNK and p38 inhibition. J. Neurosci. 33 2313–2325.

    Not in our library10.1523/jneurosci.4965-11.2013

  288. 288.

    Theodosiou A. Ashworth A. (2002 ). Differential effects of stress stimuli on a JNK-inactivating phosphatase. Oncogene 21 2387–2397.

    Not in our library10.1038/sj.onc.1205309

  289. 289.

    Tian J. Popal M. S. Zhao Y. Liu Y. Chen K. Liu Y. (2019 ). Interplay between exosomes and autophagy in cardiovascular diseases: novel promising target for diagnostic and therapeutic application. Aging Dis. 10 1302–1310.

    Not in our library10.14336/ad.2018.1020

  290. 290.

    Tong L. Prieto G. A. Kramar E. A. Smith E. D. Cribbs D. H. Lynch G. (2012 ). Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1beta via p38 mitogen-activated protein kinase. J. Neurosci. 32 17714–17724.

    Not in our library10.1523/jneurosci.1253-12.2012

  291. 291.

    Tong X. K. Hamel E. (2007 ). Transforming growth factor-beta 1 impairs endothelin-1-mediated contraction of brain vessels by inducing mitogen-activated protein (MAP) kinase phosphatase-1 and inhibiting p38 MAP kinase. Mol. Pharmacol. 72 1476–1483.

    Not in our library10.1124/mol.107.039602

  292. 292.

    Tortarolo M. Veglianese P. Calvaresi N. Botturi A. Rossi C. Giorgini A. (2003 ). Persistent activation of p38 mitogen-activated protein kinase in a mouse model of familial amyotrophic lateral sclerosis correlates with disease progression. Mol. Cell. Neurosci. 23 180–192.

    Not in our library10.1016/s1044-7431(03)00022-8

  293. 293.

    Trouillas M. Saucourt C. Duval D. Gauthereau X. Thibault C. Dembele D. (2008 ). Bcl2, a transcriptional target of p38alpha, is critical for neuronal commitment of mouse embryonic stem cells. Cell Death. Differ. 15 1450–1459.

    Not in our library10.1038/cdd.2008.63

  294. 294.

    Tsirigotis M. Baldwin R. M. Tang M. Y. Lorimer I. A. Gray D. A. (2008 ). Activation of p38MAPK contributes to expanded polyglutamine-induced cytotoxicity. PLoS One 3:e2130.

    Not in our library10.1371/journal.pone.0002130

  295. 295.

    Uhlen M. Fagerberg L. Hallstrom B. M. Lindskog C. Oksvold P. Mardinoglu A. (2015 ). Proteomics. Tissue-based map of the human proteome. Science 347:1260419.

    Not in our library10.1126/science.1260419

  296. 296.

    Umezawa H. Naito Y. Tanaka K. Yoshioka K. Suzuki K. Sudo T. (2017 ). Genetic and pharmacological inhibition of p38alpha improves locomotor recovery after spinal cord injury. Front. Pharmacol. 8:72.

    Not in our library10.3389/fphar.2017.00072

  297. 297.

    Underwood D. C. Osborn R. R. Kotzer C. J. Adams J. L. Lee J. C. Webb E. F. (2000 ). SB 239063, a potent p38 MAP kinase inhibitor, reduces inflammatory cytokine production, airways eosinophil infiltration, and persistence. J. Pharmacol. Exp. Ther. 293 281–288.

    Not in our library

  298. 298.

    van der Vaart A. Rademakers S. Jansen G. (2015 ). DLK-1/p38 MAP Kinase Signaling Controls Cilium Length by Regulating RAB-5 Mediated Endocytosis in Caenorhabditis elegans. PLoS Genet. 11:e1005733.

    Not in our library10.1371/journal.pgen.1005733

  299. 299.

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    Wittmack E. K. Rush A. M. Hudmon A. Waxman S. G. Dib-Hajj S. D. (2005 ). Voltage-gated sodium channel Nav1.6 is modulated by p38 mitogen-activated protein kinase. J. Neurosci. 25 6621–6630.

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    Wu J. Kubota J. Hirayama J. Nagai Y. Nishina S. Yokoi T. (2010 ). p38 Mitogen-activated protein kinase controls a switch between cardiomyocyte and neuronal commitment of murine embryonic stem cells by activating myocyte enhancer factor 2C-dependent bone morphogenetic protein 2 transcription. Stem Cells Dev. 19 1723–1734.

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    Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease · 2014
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    Yagasaki Y. Sudo T. Osada H. (2004 ). Exip, a splicing variant of p38alpha, participates in interleukin-1 receptor proximal complex and downregulates NF-kappaB pathway. FEBS Lett. 575 136–140.

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    Yan D. Wu Z. Chisholm A. D. Jin Y. (2009 ). The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration. Cell 138 1005–1018.

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    Yang K. Liu Y. Liu Z. Liu J. Liu X. Chen X. (2013 ). p38gamma overexpression in gliomas and its role in proliferation and apoptosis. Sci. Rep. 3:2089.

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    Yasuda S. Tanaka H. Sugiura H. Okamura K. Sakaguchi T. Tran U. (2007 ). Activity-induced protocadherin arcadlin regulates dendritic spine number by triggering N-cadherin endocytosis via TAO2beta and p38 MAP kinases. Neuron 56 456–471.

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    Yoon K. W. Yang H. S. Kim Y. M. Kim Y. Kang S. Sun W. (2017 ). CIB1 protects against MPTP-induced neurotoxicity through inhibiting ASK1. Sci. Rep. 7:12178.

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    Yoshimura Y. Terabayashi T. Miki H. (2010 ). Par1b/MARK2 phosphorylates kinesin-like motor protein GAKIN/KIF13B to regulate axon formation. Mol. Cell. Biol. 30 2206–2219.

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    Yoshioka K. Namiki K. Sudo T. Kasuya Y. (2015 ). p38alpha controls self-renewal and fate decision of neurosphere-forming cells in adult hippocampus. FEBS Open Bio 5 437–444.

    Not in our library10.1016/j.fob.2015.05.001

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    Zarubin T. Han J. (2005 ). Activation and signaling of the p38 MAP kinase pathway. Cell Res. 15 11–18.

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    Zeldich E. Chen C. D. Avila R. Medicetty S. Abraham C. R. (2015 ). The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination. J. Mol. Neurosci. 57 185–196.

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    Zhao M. New L. Kravchenko V. V. Kato Y. Gram H. di Padova F. (1999 ). Regulation of the MEF2 family of transcription factors by p38. Mol. Cell. Biol. 19 21–30.

    Not in our library10.1128/mcb.19.1.21

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    Zhao W. Liu M. Kirkwood K. L. (2008 ). p38alpha stabilizes interleukin-6 mRNA via multiple AU-rich elements. J. Biol. Chem. 283 1778–1785.

    Not in our library10.1074/jbc.m707573200

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