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Local Ca2+ signals couple activation of TRPV1 and ANO1 sensory ion channels.
Science Signaling ( IF 6.7 ) Pub Date : 2020-04-28 , DOI: 10.1126/scisignal.aaw7963
Shihab Shah 1 , Chase M Carver 2 , Pierce Mullen 1 , Stephen Milne 1 , Viktor Lukacs 1 , Mark S Shapiro 2 , Nikita Gamper 1, 3
Affiliation  

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.

中文翻译:

局部 Ca2+ 信号耦合激活 TRPV1 和 ANO1 感觉离子通道。

ANO1 (TMEM16A) 是一种 Ca2+ 激活的 Cl- 通道 (CaCC),在外周体感神经元中表达,可被疼痛(有害)刺激激活。这些神经元还表达可激活 ANO1 的 Ca2+ 可渗透通道和有害热传感器 TRPV1。在这里,我们揭示了大鼠背根神经节 (DRG) 神经元中 TRPV1-ANO1 通道耦合的复杂机制。同时对 CaCC 活性和 Ca2+ 动力学进行光学监测表明,TRPV1 配体辣椒素激活了 CaCC。然而,内质网 (ER) Ca2+ 存储的耗尽减少了辣椒素诱导的 Ca2+ 增加和 CaCC 激活,表明 ER Ca2+ 释放有助于 TRPV1 诱导的 CaCC 激活。在暴露于细胞不可渗透的 TRPV1 配体的神经元中,质膜定位的 TRPV1 通道通过 ER 定位的 Ca2+ 传感器证明了 ER 存储耗尽。邻近连接分析表明,ANO1、TRPV1 和 IP3 受体 IP3R1 经常彼此靠近。随机光学重建显微镜 (STORM) 证实了 DRG 神经元中所有三个通道之间的密切关联。总之,我们的数据揭示了 DRG 神经元中含有 ANO1 的多通道纳米域的存在,并表明 TRPV1 和 ANO1 之间的耦合需要 ER Ca2+ 释放,这可能是增强 ANO1 激活所必需的。随机光学重建显微镜 (STORM) 证实了 DRG 神经元中所有三个通道之间的密切关联。总之,我们的数据揭示了 DRG 神经元中含有 ANO1 的多通道纳米域的存在,并表明 TRPV1 和 ANO1 之间的耦合需要 ER Ca2+ 释放,这可能是增强 ANO1 激活所必需的。随机光学重建显微镜 (STORM) 证实了 DRG 神经元中所有三个通道之间的密切关联。总之,我们的数据揭示了 DRG 神经元中含有 ANO1 的多通道纳米域的存在,并表明 TRPV1 和 ANO1 之间的耦合需要 ER Ca2+ 释放,这可能是增强 ANO1 激活所必需的。
更新日期:2020-04-28
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