Expression of Ca2+‐permeable two‐pore channels rescues NAADP signalling in TPC‐deficient cells

Abstract

The second messenger NAADP triggers Ca 2+ release from endo‐lysosomes. Although two‐pore channels (TPCs) have been proposed to be regulated by NAADP, recent studies have challenged this. By generating the first mouse line with demonstrable absence of both Tpcn1 and Tpcn2 expression (Tpcn1/2 −/− ) , we show that the loss of endogenous TPCs abolished NAADP‐dependent Ca 2+ responses as assessed by single‐cell Ca 2+ imaging or patch‐clamp of single endo‐lysosomes. In contrast, currents stimulated by PI(3,5)P 2 were only partially dependent on TPCs. In Tpcn1/2 −/− cells, NAADP sensitivity was restored by re‐expressing wild‐type TPCs, but not by mutant versions with impaired Ca 2+ ‐permeability, nor by TRPML1. Another mouse line formerly reported as TPC‐null likely expresses truncated TPCs, but we now show that these truncated proteins still support NAADP‐induced Ca 2+ release. High‐affinity [ 32 P]NAADP binding still occurs in Tpcn1/2 −/− tissue, suggesting that NAADP regulation is conferred by an accessory protein. Altogether, our data establish TPCs as Ca 2+ ‐permeable channels indispensable for NAADP signalling.

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Cited by papers we hold 4

• Lysosomal Biology and Function: Modern View of Cellular Debris Bin · 2020
  No notice
• Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function · 2020
  No notice
• IP3 Receptor-Mediated Calcium Signaling and Its Role in Autophagy in Cancer · 2017
  No notice
• Intracellular sphingosine releases calcium from lysosomes · 2015
  No notice

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