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TMEM120A/TACAN 抑制机械激活的 PIEZO2 通道。

TMEM120A/TACAN inhibits mechanically activated PIEZO2 channels.

机构信息

Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ.

出版信息

J Gen Physiol. 2022 Aug 1;154(8). doi: 10.1085/jgp.202213164. Epub 2022 Jul 12.

DOI:10.1085/jgp.202213164
PMID:35819364
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9280072/
Abstract

PIEZO2 channels mediate rapidly adapting mechanically activated currents in peripheral sensory neurons of the dorsal root ganglia (DRG), and they are indispensable for light touch and proprioception. Relatively little is known about what other proteins regulate PIEZO2 activity in a cellular context. TMEM120A (TACAN) was proposed to act as a high threshold mechanically activated ion channel in nociceptive DRG neurons. Here, we find that Tmem120a coexpression decreased the amplitudes of mechanically activated PIEZO2 currents and increased their threshold of activation. TMEM120A did not inhibit mechanically activated PIEZO1 and TREK1 channels and TMEM120A alone did not result in the appearance of mechanically activated currents above background. Tmem120a and Piezo2 expression in mouse DRG neurons overlapped, and siRNA-mediated knockdown of Tmem120a increased the amplitudes of rapidly adapting mechanically activated currents and decreased their thresholds to mechanical activation. Our data identify TMEM120A as a negative modulator of PIEZO2 channel activity, and do not support TMEM120A being a mechanically activated ion channel.

摘要

PIEZO2 通道介导背根神经节（DRG）外周感觉神经元中的快速适应机械激活电流，对于轻触和本体感觉是必不可少的。关于其他哪些蛋白质在细胞环境中调节 PIEZO2 活性，人们知之甚少。TMEM120A（TACAN）被提议作为伤害感受性 DRG 神经元中的高阈值机械激活离子通道发挥作用。在这里，我们发现 TMEM120A 的共表达降低了机械激活 PIEZO2 电流的幅度，并增加了其激活的阈值。TMEM120A 不抑制机械激活的 PIEZO1 和 TREK1 通道，并且 TMEM120A 本身不会导致背景以上的机械激活电流的出现。Tmem120a 和 Piezo2 在小鼠 DRG 神经元中的表达重叠，siRNA 介导的 Tmem120a 敲低增加了快速适应机械激活电流的幅度，并降低了其机械激活的阈值。我们的数据将 TMEM120A 鉴定为 PIEZO2 通道活性的负调节剂，并不支持 TMEM120A 作为机械激活离子通道。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/908c/9280072/9e3db2222a8b/JGP_202213164_FigS7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/908c/9280072/6ef204c6d7b7/JGP_202213164_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/908c/9280072/7c050b8d0bab/JGP_202213164_FigS4.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/908c/9280072/9e3db2222a8b/JGP_202213164_FigS7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/908c/9280072/ba1e4c7b4f50/JGP_202213164_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/908c/9280072/22949d213162/JGP_202213164_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/908c/9280072/b5305c25caa9/JGP_202213164_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/908c/9280072/bf8355f98c67/JGP_202213164_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/908c/9280072/6ef204c6d7b7/JGP_202213164_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/908c/9280072/7c050b8d0bab/JGP_202213164_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/908c/9280072/b3b61d061806/JGP_202213164_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/908c/9280072/efbd8cd81aa9/JGP_202213164_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/908c/9280072/3dd31938de72/JGP_202213164_Fig3.jpg
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Cryo-EM structures of human TMEM120A and TMEM120B.人类跨膜蛋白120A（TMEM120A）和跨膜蛋白120B（TMEM120B）的冷冻电镜结构
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