Research ArticleIon Channels

Local Ca2+ signals couple activation of TRPV1 and ANO1 sensory ion channels

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Science Signaling  28 Apr 2020:
Vol. 13, Issue 629, eaaw7963
DOI: 10.1126/scisignal.aaw7963

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Boosting the Ca2+ signal for nociception

The Ca2+-activated Cl channel ANO1 promotes nociception, the perception of pain. The nonselective cation channel TRPV1 has been proposed to be the source of Ca2+ that activates ANO1, but the amount of Ca2+ that TRPV1 allows into pain-transmitting DRG neurons is thought to be insufficient to activate ANO1. Shah et al. found that TRPV1 triggered Ca2+ release from the ER through an IP3 receptor isoform. Imaging techniques showed that ANO1, TRPV1, and the IP3 receptor clustered in close proximity to each other in pain-transmitting DRG neurons. These results provide insight into the molecular mechanisms underlying nociception.

Abstract

ANO1 (TMEM16A) is a Ca2+-activated Cl channel (CaCC) expressed in peripheral somatosensory neurons that are activated by painful (noxious) stimuli. These neurons also express the Ca2+-permeable channel and noxious heat sensor TRPV1, which can activate ANO1. Here, we revealed an intricate mechanism of TRPV1-ANO1 channel coupling in rat dorsal root ganglion (DRG) neurons. Simultaneous optical monitoring of CaCC activity and Ca2+ dynamics revealed that the TRPV1 ligand capsaicin activated CaCCs. However, depletion of endoplasmic reticulum (ER) Ca2+ stores reduced capsaicin-induced Ca2+ increases and CaCC activation, suggesting that ER Ca2+ release contributed to TRPV1-induced CaCC activation. ER store depletion by plasma membrane–localized TRPV1 channels was demonstrated with an ER-localized Ca2+ sensor in neurons exposed to a cell-impermeable TRPV1 ligand. Proximity ligation assays established that ANO1, TRPV1, and the IP3 receptor IP3R1 were often found in close proximity to each other. Stochastic optical reconstruction microscopy (STORM) confirmed the close association between all three channels in DRG neurons. Together, our data reveal the existence of ANO1-containing multichannel nanodomains in DRG neurons and suggest that coupling between TRPV1 and ANO1 requires ER Ca2+ release, which may be necessary to enhance ANO1 activation.

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