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GPCR Signaling Regulation: The Role of GRKs and Arrestins

Vsevolod V. Gurevich, Eugenia V. Gurevich

Frontiers in Pharmacology · 2019 · Review · CC BY

doi:10.3389/fphar.2019.00125

Abstract

Every animal species expresses hundreds of different G protein-coupled receptors (GPCRs) that respond to a wide variety of external stimuli. GPCRs-driven signaling pathways are involved in pretty much every physiological function and in many pathologies. Therefore, GPCRs are targeted by about a third of clinically used drugs. The signaling of most GPCRs via G proteins is terminated by the phosphorylation of active receptor by specific kinases (GPCR kinases, or GRKs) and subsequent binding of arrestin proteins, that selectively recognize active phosphorylated receptors. In addition, GRKs and arrestins play a role in multiple signaling pathways in the cell, both GPCR-initiated and receptor-independent. Here we focus on the mechanisms of GRK- and arrestin-mediated regulation of GPCR signaling, which includes homologous desensitization and redirection of signaling to additional pathways by bound arrestins.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

GPCR Signaling Via G Proteins

G protein-coupled receptors are the largest family of signaling proteins. Structurally, the cores of all GPCRs are very similar: extracellular N-terminus, seven membrane-spanning α-helices (TM), and intracellular C-terminus, with variable extracellular and intracellular elements. GPCRs mediate cellular response to various stimuli, from light and odorants to hormones, neurotransmitters, and even extracellular protease activity and calcium. GPCRs are usually localized on the plasma membrane, serving as “eyes and ears” of the cell. Accordingly, GPCRs have ligand-binding elements exposed on the extracellular side. Most receptors belong to class A that have a ligand-binding pocket between the helices, which could be either close to the extracellular surface or buried almost to half the depth of the membrane. Even covalently attached 11-cis-retinal in the light receptor rhodopsin sits in a pocket similar to those of the receptors that bind dissociable small molecule ligands. Class B GPCRs interact with peptides. These receptors have large N-termini, which contain the high-affinity part of the ligand-binding site, with the pocket between helices constituting the lower affinity part. Class C GPCRs are dimers, consisting of two 7TM units, with ligand-binding pocket localized on a separate extracellular Venus flytrap domain homologous to bacterial proteins involved in transporting amino acids and ions. In class C GPCRs many allosteric modulators bind to the pocket between helices in the 7TM part, so that after the deletion of the extracellular elements the remaining heptahelical domain functions pretty much like a class A receptor binding allosteric regulators as ligands. GPCR orthosteric (i.e., binding to the site natural ligand occupies) ligands fall into three categories: activating (agonists), inactivating (inverse agonists that suppress constitutive activity), and neutral (antagonists, that occupy the site but do nothing else). Most natural ligands are agonists, but some are antagonists (e.g., agouti and agouti-related peptide are antagonists of melanocortin receptors). Covalently attached to rhodopsin 11-cis-retinal is an inverse agonist, which ensures virtually zero constitutive activity of rhodopsin in the dark, whereas a photon of light converts it into all-trans-retinal, which is an agonist that also remains covalently attached.

G protein-coupled receptor activation is accompanied by the outward movement of transmembrane helices V and VI, which creates a cavity on the cytoplasmic side of the heptahelical domain. Activation-induced movement appears to be smaller in case of Gi-coupled GPCRs, as compared to Gs-coupled. Recent structural studies showed that this cavity serves as a docking site for the heterotrimeric G proteins of all subtypes. Agonist-activated GPCRs act as guanyl nucleotide exchange factors for heterotrimeric G proteins. In the receptor-bound G protein its nucleotide-binding pocket opens, which results in the loss of GDP occupying this site in the inactive form, and binding of GTP, which is much more abundant in the cytoplasm. GTP-liganded G protein α-subunit then dissociates from the receptor and βγ-subunit, whereupon both G protein subunits bind their respective effectors. Freed active receptor can bind and activate another G protein molecule, which provides signal amplification at this level. The effectors of G proteins are either ion channels or enzymes, so that the activation of a single effector molecule induces the movement of numerous ions across plasma membrane or the conversion of many substrate molecules into product, providing further signal amplification. Among GPCR-driven systems signal amplification is the greatest in rod photoreceptors, which gives these cells single photon sensitivity. However, everything the cell does costs energy. So, as soon as the cell gets the message, it makes biological sense to stop signaling. In case of GPCRs, rapid signal turnoff is accomplished by a conserved two-step mechanism: receptor phosphorylation by GRKs followed by arrestin binding.

Phosphorylation of Active Receptors by GRKs

Activation-induced rhodopsin phosphorylation was discovered in the early 1970s, before it became clear that there is a GPCR family to which rhodopsin belongs. Subsequent studies revealed that rhodopsin kinase binds rhodopsin-containing membranes only upon its activation by illumination. Later another receptor kinase, originally named β-adrenergic receptor kinase, was discovered, which specifically phosphorylated activated β2-adrenergic receptor (β2AR). That kinase was also shown to phosphorylate rhodopsin in activation-dependent manner. The cloning and sequencing of this kinase (modern systematic name GRK2, whereas rhodopsin kinase is now called GRK1 ) suggested that there is a family of GRKs likely targeting different GPCRs.

The key question that needed to be answered was why these kinases specifically phosphorylate active receptors, whereas other protein kinases known at the time simply recognized specific sequences within targeted proteins. This question was answered in the visual system, where by proteolysis one could eliminate the rhodopsin C-terminus with all phosphorylation sites, while leaving the rest of the rhodopsin molecule as a functional light receptor. Rhodopsin kinase was shown to be activated by physical interaction with light-activated rhodopsin, whereupon it could phosphorylate anything accessible, including exogenous peptides. Similar activation mechanism was described for GRK2. Apparently, when GRK binds a full-length GPCR, the receptor activates it. Parts of that same receptor happen to be in the vicinity and are therefore phosphorylated by the kinase. However, when the receptor is crowded, like rhodopsin in rod disk membranes, where rhodopsin molecules cover about half of the area, inactive receptors can come close by diffusion and get phosphorylated by the kinase activated by the active receptor. This high-gain phosphorylation, which is best observed when a very small fraction of rhodopsin molecules is activated, essentially confirms the mechanism of GRK activation. This mechanism, the phosphorylation of inactive pigment molecules by GRK1 activated by bleached rhodopsin, was further supported by detected phosphorylation of an inactive cone pigment co-expressed in rods with rhodopsin.

GRKs are soluble proteins, so they need specific mechanisms to bring them to the vicinity of membrane-embedded GPCRs. Visual GRK-1 and -7 are prenylated at their C-termini, which ensures their constitutive membrane localization. The pleckstrin homology (PH) domain of GRK2/3 binds Gβγ. GRK2 was even crystallized in complex with Gβγ bound to its PH domain. The Gβγ binding recruits GRK2/3 to the membrane, where the receptors reside. Thus, Gβγ released after G protein activation by a GPCR helps to recruit GRK2/3 to the receptor to shut off signaling. It has recently been reported that the dopamine D2 receptor can recruit GRK2 even without G protein activation, although this observation is puzzling considering that no agonist-dependent phosphorylation of the receptor was observed. Interestingly, the expression of the plekstrin homology domain of GRK2 separately from the rest of the molecule suppresses Gβ-mediated signaling in the cell. The GRK4/5/6 subfamily lacks the PH domain as well as the C-terminal prenylation. Instead, the GRKs of this subfamily associate with the plasma membrane via palmitoylation of their C-terminal cysteines and/or via an amphipathic helix interacting with the membrane phospholipids ( and references therein).

Interestingly, out of three branches of the GRK family, The GRK1/7, GRK2/3, and GRK/4/5/6, only the first two appear to be activated exclusively by the binding to active GPCRs. GRK4 constitutively phosphorylates the dopamine D1 receptor. GRK5 was shown to be activated by phospholipids in vitro and GRK5 and closely related GRK6 phosphorylate even inactive GPCRs both in vitro and in live cells. However, the structural data on the GRK-GPCR complexes suggest that GRK1, as well as GRK5 engage the same inter-helical cavity in active GPCRs that is part of the docking site of G proteins and arrestins. In agreement with this, engineered phosphorylation-independent arrestin-2 was shown to compete with GRK2 for the β2AR, indicating that the binding sites on GPCRs used by GRKs and arrestins bind overlap and include the cavity on the cytoplasmic side of GPCRs that opens upon receptor activation.

Although phosphorylation of rhodopsin and β2AR reduced signaling via G proteins, it did not stop it. So, another set of players was suspected. These players turned out to be arrestins (Figure 1).

Arrestins Block G Protein Coupling

Preferential binding of arrestins to their cognate receptors when they are active and phosphorylated at the same time was demonstrated directly in case of visual arrestin-1 and non-visual arrestin-2. The role of arrestin-1 (called 48 kDa protein at the time of discovery) in preventing the coupling of phosphorylated rhodopsin to its cognate G protein, transducin, was established in mid-1980s. Later is shown independently by two labs that visual arrestin-1 does that by successfully competing with transducin for the light-activated phosphorylated rhodopsin. The need of an arrestin-like protein in the homologous desensitization of β2AR was shown using purified receptor and GRK2 of different levels of purity. It turned out that while highly purified GRK2 phosphorylated the receptor better than partially purified preparation, it failed to significantly suppress its coupling to the cognate G protein, Gs. The addition of purified visual arrestin (arrestin-1 in current systematic nomenclature) significantly enhanced the desensitizing effect of receptor phosphorylation by GRK2, which suggested that non-visual homolog of arrestin-1 might be required for homologous desensitization of the non-rhodopsin GPCRs. Soon thereafter the first non-visual arrestin was cloned. It was termed β-arrestin because it clearly preferred β2AR over rhodopsin. The second non-visual arrestin was cloned soon after the first, and called β-arrestin2, whereas the first one was retroactively renamed β-arrestin1. The second non-visual subtype was also cloned from human thyroid and named hTHY-ARRX. When it was cloned for the third time, a systematic arrestin nomenclature, with the number indicating the order of cloning, was proposed, which made this member of the family arrestin-3. Interestingly, only one additional arrestin, cone photoreceptor-specific arrestin-4, was found in mammals. Thus, hundreds of GPCR subtypes expressed by most mammals (from ∼500 in dolphins and ∼800–1,200 in primates including humans to >3,400 in elephants; sevens.cbrc.jp), are served by only four arrestin proteins, two of which (arrestin-1 and -4) are specialized visual, they are expressed in photoreceptor cells in the retina and bind photopigments, leaving the two non-visual subtypes for the rest of GPCRs. The role of arrestins in terminating G protein-mediated GPCR signaling is well established. Recent structural data revealed the molecular basis of the competition between G proteins and arrestins: both engage the same inter-helical cavity on the cytoplasmic side of the receptor, so that the binding of one precludes the binding of another. Bound G proteins readily dissociate from the receptor in the presence of GTP, whereas arrestins do not. Thus, in case of active phosphorylated GPCRs, which arrestins bind with high affinity, arrestins easily win in the competition with G proteins. However, in addition to the inter-helical cavity, which is a shared docking site of G protein and arrestins, the latter tightly bind receptor-attached phosphates that fit into positive patches on the arrestin surface. This dual-site binding, predicted in 1993 based on arrestin mutagenesis, creates a possibility that arrestin might engage the receptor via only one site. Indeed, it was shown that, at least in case of mutant GPCRs and/or arrestins, the latter can engage solely the phosphorylated receptor C-terminus, leaving the inter-helical cavity accessible for a G protein. In this situation “super-complexes” that include a single GPCR simultaneously interacting with G protein and arrestin were observed. Recent study of different subtypes of neuropeptide Y receptors suggests that this mechanism might operate in case of at least some wild type GPCRs. However, it appears that simultaneous arrestin interaction with both inter-helical cavity and phosphorylated parts of the receptor, which precludes G protein binding, is the rule, rather than an exception. This mode of arrestin binding is the basis of homologous GPCR desensitization, ensuring direct competition of arrestins with G proteins.

Both non-visual arrestin subtypes effectively bind clathrin and its adaptor AP2 via specific sites in their C-termini, which are made more accessible by the release of the C-terminus upon GPCR binding, similar to the rhodopsin binding-induced release of the C-terminus of visual arrestin-1. Thus, non-visual arrestins not only block receptor coupling to the G proteins, but also facilitate GPCR internalization via coated pits (reviewed in ), further reducing cell responsiveness. Interestingly, visual arrestin-1 does not have a clathrin-binding site, although it has a relatively low affinity AP2 binding site. It is likely a relic, as all arrestins apparently arose from an ancestral universal form, similar to a single arrestin in ascidian Ciona officinalis, which serves as visual in the eyes of its tadpole and as non-visual in the sessile blind adult, where it likely promotes GPCR internalization.

Arrestin-Mediated Signaling

In addition to stopping (“arresting,” hence the name) GPCR signaling via G proteins, in the last two decades arrestins have been proposed to serve as signal transducers in their own right [reviewed in;;; Figure 1]. The first signaling function of arrestins was described in 1999: receptor-bound arrestins were found to promote Src-dependent activation of pro-proliferative MAP kinases ERK1/2. Soon arrestin-3 (but not closely related arrestin-2) was found to scaffold ASK1-MKK4/7-JNK3 cascade, also in receptor-dependent manner. Then both non-visual arrestins upon GPCR binding were shown to scaffold yet another three-tiered MAP kinase cascade, c-Raf1-MEK1-ERK1/2. This finding revealed a previously unappreciated mechanism of GPCR-dependent facilitation of ERK1/2 activation. The number of non-receptor binding partners of non-visual arrestins kept increasing, culminating in a comprehensive proteomics study that described more than a hundred proteins that bind each of the non-visual subtypes, many of which are bona fide signaling proteins. The results of protein knockdown using siRNAs even suggested that arrestin-mediated signaling to ERK1/2 is G protein-independent. However, numerous pathways lead to the activation of ERKs, and many of them, such as receptor tyrosine kinase-dependent, are not even GPCR-driven. Recent findings indicate that in total absence of G protein activity (“zero functional G cells”) due to genetic knockout of members of Gs, Gq, and G12/13 families and inactivation of Gi family members by pertussis toxin, arrestin-mediated signaling in response to GPCR activation cannot be detected. In contrast, in arrestin-2/3 knockout cells ERK1/2 phosphorylation in response to the activation of several GPCRs, which was often considered a hallmark of arrestin-mediated signaling, is similar to that in parental cells with full complement of non-visual arrestins. These data are incompatible with the idea that arrestin-mediated signaling is G protein-independent, but do not contradict the notion that arrestin-mediated signaling actually exists, as was shown yet again by a recent study that used three independently generated arrestin-2/3 knockout cell lines. In fact, the role of arrestins in enhancing ERK1/2 activation in the presence of G proteins in case of some GPCRs was documented in the study designed to demonstrate G protein dependence of GPCR signaling.

The major aspect overlooked in virtually all studies of arrestin-mediated signaling is signal initiation. MAPK kinase activation cascades are highly conserved three-tier signaling modules consisting in general terms of upstream MAP3Ks, intermediate MAP2Ks, and downstream MAPKs. MAP3Ks and MAP2Ks activate their downstream target kinases by phosphorylating their activation loops. MAPKs ultimately phosphorylate various nuclear and cytoplasmic proteins to elicit cellular response. Scaffold proteins, such as arrestins, bring the kinases close to each other, thereby facilitating signal transduction. However, the signaling only occurs when the upstream-most MAP3Ks are activated, and arrestins were never implicated in this event. It is entirely possible that before arrestin-mediated scaffolding has a chance to facilitate signaling, MAP3Ks must be activated by arrestin-independent mechanisms, which can be G protein-dependent in case of GPCRs, or G protein- and GPCR-independent in case of growth factor receptors and integrins. This aspect of arrestin-mediated scaffolding needs to be studied experimentally.

GPCR-Independent Signaling Functions of GRKs

GRKs have been reported to phosphorylate and thus regulate via phosphorylation numerous non-GPCR substrates, including receptor tyrosine kinases, single transmembrane domain serine/threonine kinases, death receptors, toll-like receptors, transcription factors, various adapter proteins, cytosolic, nuclear and cytoskeletal proteins (for review see ). Although in most cases the functional role of regulation via GRK-dependent phosphorylation remains poorly understood, the mere number of targets suggests that, in addition to playing the key role in controlling the GPCR signaling, GRKs might play important roles in cell growth, attachment and motility, cell death, proliferation and survival, immunity, cancer, as well as other pathological conditions. One example of such regulation is GRK5-dependent phosphorylation of class II histone deacetylase 5 (HDAC5), which plays a role in pathological cardiac hypertrophy. Another interesting substrate of GRK-dependent phosphorylation is the synuclein family comprising α-, β-, and γ-synucleins, small proteins with poorly defined functions. GRK2 preferentially phosphorylates α- and β-synucleins, whereas α-synuclein is the best substrate of GRK5. The great importance of α-synuclein, which is enriched in the presynaptic terminals in the nervous system, stems from its role in sporadic Parkinson’s disease as the main component of Lewy bodies, a hallmark feature of the disorder, as well as from its genetic association with a familial form of the disease.

In addition to regulating multiple non-GPCR signaling pathways via phosphorylation, GRKs can control signaling in phosphorylation-independent manner via direct protein-protein interaction. The best studied mode of such regulation is via the function of the GRK RGS homology (RH) domain. The RH domain of GRKs 2/3 acts in a manner similar to other RGS proteins by binding active Gαq/11. In contrast to canonical RGS proteins, RH domains of GRKs possess only weak ability to activate intrinsic GTPase of G proteins, but instead reduce the Gq/11-mediated signaling mostly by sequestering active Gαq/11 or directly blocking the receptor. Although all GRK isoforms are equipped with the RH domain, only the RH domain of GRKs 2/3 appears to be functional, whereas those of other GRKs seem to be unable to interact with any G protein, for they are missing the key binding residues.

GRKs 2/3 possess the PH domain in their C-terminus capable of binding Gβγ. In addition to mediating the recruitment of the kinases to the plasma membrane upon receptor activation, it also regulates the Gβγ-dependent signaling in the same manner as RH domain regulates the Gq/11-mediated signaling: by sequestering Gβγ and inhibiting Gβγ-mediated signaling processes. This mechanism has been described for G protein-coupled inwardly rectifying potassium channels (GIRK) activated by adenosine A1 and μ-opioid receptors and for κ-opioid receptors. GRKs are able to perform other protein binding and/or scaffolding functions (for details see ). For example, GRK5 biding to calmodulin assists in the nuclear translocation associated with the cardiac hypertrophy. Furthermore, in addition to phosphorylating HDAC5 in the nucleus, GRK5 contributes to pathological cardiac hypertrophy by activating nuclear factor of activated T cells (NFAT) transcription factor in phosphorylation-independent manner via direct binding. Thus, GRK functions requiring the kinase activity and phosphorylation-independent actions go hand in hand in physiological and pathological processes.

Some of these functions are mediated by GRK interacting proteins (GITs), which are themselves large multidomain scaffolding proteins interacting with multiple partners and playing important role in numerous cellular processes. The involvement of GRKs via their phosphorylation-independent scaffolding function in multiple signaling events in cells led to a suggestion that GRKs might, in concert with arrestins, serve as a critical node within the complex signaling network and a play a role in multiple conditions and/or pathologies, such as aging, cardiovascular and neurodegenerative disorders.

GPCR-Independent Signaling Functions of Arrestins

Arrestins also serve as signaling molecules independently of GPCRs (Figure 1). Arrestin-3-dependent facilitation of JNK3 activation was first shown to be independent of GPCRs as early as 2001. This was later confirmed by the use of arrestin mutants that do not bind receptors and by reconstitution of MKK4/7-JNK3 modules with arrestin-3 using purified proteins in vitro in the absence of GPCRs. A short arrestin-3-derived peptide lacking most known receptor-binding elements was found to facilitate JNK3 activation in vitro and in living cells. Interestingly, the measurements of the affinities of active and inactive kinases of the ASK1-MKK4/7-JNK3 cascade suggest that the activation of MKK4, MKK7, and JNK3 by phosphorylation reduces their binding to arrestin-3. This reduction in binding affinity is the most striking in case of JNK3, suggesting that activated (doubly phosphorylated) JNK3 likely dissociates, freeing the place for another molecule of inactive JNK3 to bind. This “conveyor belt” mechanism allows the complex of arrestin-3 with upstream kinases to sequentially activate several JNK3 molecules, thereby amplifying the signal. It would be interesting to test whether other MAP kinase scaffolds also employ similar amplification mechanism. The critical role of caspase-cleaved arrestin-2 in programmed cell death also did not appear to depend on receptor binding. Caspase cleavage of the other non-visual subtype, arrestin-3, which generates anti-apoptotic arrestin-3-(1-366) fragment, also does not require GPCR activation. The function of both non-visual arrestins in focal adhesion disassembly or in the activation of small G proteins that regulate cytoskeleton also did not require arrestin interactions with the receptor.

Thus, widespread belief that arrestin-mediated signaling is always GPCR-driven appears to be wrong. In fact, there are known non-receptor partners that free arrestins, including arrestin mutants that do not interact with GPCRs, bind with higher affinity than receptor-bound (presumably “active”) arrestins. These include E3 ubiquitin ligases Mdm2 and parkin, whereas all functional forms of arrestin-3 appear to bind JNK3 comparably. So, the question what is the “active” conformation of arrestins and whether there are several “active” conformations facilitating different branches of signaling, needs to be answered experimentally.

Potential Routes of Intervention

Elucidation of every molecular mechanism of cellular functions paves the way to devising tools that affect this mechanism for therapeutic purposes. GPCR desensitization via GRKs and arrestins, as well as arrestin-dependent signaling are no exceptions. Arguably, congestive heart failure is the most studied condition where GPCR desensitization plays a role in the pathology (reviewed in ). Heart failure manifests itself as the loss of heart responsiveness to pro-contractile stimuli. This is primarily adrenalin, which acts via β-adrenergic receptors, both β1 and β2 subtypes. Both appear to undergo excessive desensitization mediated by GRK2. When GRK2 ability to suppress β-adrenergic signaling is reduced by overexpression of GRK2 C-terminus that outcompetes endogenous full-length kinase for the G protein βγ-subunit, which targets GRK2 to the plasma membrane where β-adrenergic receptors reside, heart failure is alleviated. This does not appear to cause many side effects, in contrast to inhibitors of ubiquitously expressed GRK2 (even if selective ones were available), that would likely indiscriminately affect the desensitization of many GPCRs in various cell types. An alternative approach that has not been tested experimentally so far would be to express in the heart one of existing arrestin mutants that binds unphosphorylated β-adrenergic receptors. At least one of these mutants was shown to directly compete with GRK2 for the receptor and greatly facilitate receptor recycling back to the plasma membrane, where it can signal.

These “enhanced” phosphorylation-independent versions of non-visual arrestins were also proposed as tools to compensate for excessive GPCR signaling in diseases associated with activating receptor mutations and/or defects in receptor phosphorylation. This approach was so far tested only in the visual system, where enhanced arrestin-1 improved photoreceptor performance and survival in mouse models with defective rhodopsin phosphorylation. However, for this purpose enhanced mutants of non-visual arrestins must be rendered specific for particular GPCRs to avoid their effect on the signaling of perfectly normal GPCRs co-expressed in the same cell. The first attempts to develop receptor-specific non-visual arrestins appear promising, because as few as two mutations on the receptor-binding surface yielded mutants with ∼50–60-fold preference for some GPCRs over others. Manipulation of the receptor-binding surface of arrestins was also shown to change their selectivity for particular functional forms of the receptor. However, the ability of these receptor subtype-specific forms to selectively suppress signaling by certain GPCRs without affecting others co-expressed in the same cell still remains to be tested.

Another therapeutic approach that needs to be tested is the use of signaling-biased arrestins. WT non-visual arrestins have a lot of functions: they bind hundreds of different GPCRs and dozens of non-receptor signaling proteins, affecting multiple branches of cellular signaling. Thus, an increase or decrease of WT arrestin expression in cells cannot serve a specific function: too many things would change. However, quite a few arrestin mutants where individual functions are suppressed or destroyed were constructed: forms that do not bind GPCRs [KNC mutants], mutants with disabled clathrin and/or AP2 binding sites, arrestin-3 variant that does not facilitate JNK activation, arrestin-2 mutants that do not promote ERK1/2 activation due to reduced binding of upstream kinases MEK1 or c-Raf1. One drawback is that in some cases mutations affect not only the intended function, but others, as well. For example, arrestin-3-KNC, despite normal or even enhanced binding to the kinases of ASK1-MKK4/7-JNK3 cascade, fails to facilitate the activation of JNK3, and even acts as a silent scaffold, suppressing JNK3 activation by WT arrestin-3. It is hardly practical to test every mutant for all the functions that corresponding WT arrestin fulfills, so these mutants might have limited therapeutic usability. In contrast, monofunctional elements extracted from multi-functional arrestin proteins hold greater promise. So far two of these were constructed. Separated arrestin-2 C-terminus carrying both clathrin and AP2 binding sites, effectively outcompetes the arrestin-receptor complexes in coated pits, suppressing arrestin-dependent GPCR endocytosis in cells. Arrestin-3 N-terminal peptide (T1A, which is only 25 residues long and lacks most receptor-binding elements) serves as a scaffold for the ASK1/MKK4/7-JNK3 cascade, facilitating JNK3 activation in vitro and in cells. Thus, at least two arrestin functions can be manipulated independently of the others. Of course, this is just the beginning, but these findings are encouraging.

All of the examples above imply gene therapy, which is currently in its infancy. Theoretically, identification of arrestin sites responsible for the binding of any particular partner enable the search for small molecules that can bind to the site and selectively inhibit an individual interaction. This avenue also needs to be explored, although it might yield fewer useful molecules than one would expect. Protein-protein interaction sites often involve relatively flat surfaces or disordered protein elements, both of which are notoriously hard to target with small molecules.

To summarize, selective regulation of GRKs and arrestins appears promising as a therapeutic approach. Many avenues of this regulation, involving both conventional small molecule therapeutics and gene therapy, must be explored.

Author’s Note

We use systematic names of arrestin proteins, where the number after the dash indicates the order of cloning: arrestin-1 (historic names S-antigen, 48 kDa protein, visual or rod arrestin), arrestin-2 (β-arrestin or β-arrestin1), arrestin-3 (β-arrestin2 or hTHY-ARRX), and arrestin-4 (cone or X-arrestin).

Author Contributions

VG and EG wrote the manuscript.

Conflict of Interest Statement

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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