STIM1 and ORAI1 form a novel cold transduction mechanism in sensory and sympathetic neurons.
STIM1 and ORAI1 form a novel cold transduction mechanism in sensory and sympathetic neurons.
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DOI：
10.15252/embj.2022111348
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发表时间：
2023-02-01
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周围感觉神经上的TRPM8离子通道可以感觉到适度的凉爽，但检测到有害感冒的机制仍然难以捉摸。在这里，我们展示了躯体感觉神经元和交感神经元表达两种不同的机制来检测伤寒。在第一种情况下，冷抑制背景外向电流导致膜去极化，激活通过电压依赖钙(Cav)通道的内向电流。第二种冷激活机制独立于膜电压，被ORAI离子通道阻滞剂和STIM1下调抑制，并通过ORAI1和STIM1的共同表达在HEK293细胞中重现。利用全内反射荧光显微镜，我们发现寒冷导致STIM1与ORAI1离子通道聚集并激活，其机制类似于潜在的商店操作的钙进入(SOCE)，但直接被寒冷激活，而不是通过清空钙库。这一新的机制可以解释寒冷诱导血管扩张(CIVD)的现象，即极端寒冷增加血液流动，以保护周围组织的完整性。感觉神经元和交感神经元通过冷诱导的STIM1-ORAI1聚集，激活钙离子通过ORAI1通道的内流，对非常低的温度做出反应。
Moderate coolness is sensed by TRPM8 ion channels in peripheral sensory nerves, but the mechanism by which noxious cold is detected remains elusive. Here, we show that somatosensory and sympathetic neurons express two distinct mechanisms to detect noxious cold. In the first, inhibition by cold of a background outward current causes membrane depolarization that activates an inward current through voltage‐dependent calcium (CaV) channels. A second cold‐activated mechanism is independent of membrane voltage, is inhibited by blockers of ORAI ion channels and by downregulation of STIM1, and is recapitulated in HEK293 cells by co‐expression of ORAI1 and STIM1. Using total internal reflection fluorescence microscopy we found that cold causes STIM1 to aggregate with and activate ORAI1 ion channels, in a mechanism similar to that underlying store‐operated calcium entry (SOCE), but directly activated by cold and not by emptying of calcium stores. This novel mechanism may explain the phenomenon of cold‐induced vasodilation (CIVD), in which extreme cold increases blood flow in order to preserve the integrity of peripheral tissues. Sensory and sympathetic neurons respond to very low temperatures by cold‐induced STIM1‐ORAI1 clustering that activates an influx of calcium ions through ORAI1 channels.