An external sodium ion binding site controls allosteric gating in TRPV1 channels
An external sodium ion binding site controls allosteric gating in TRPV1 channels
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DOI：
10.7554/elife.13356
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发表时间：
2016-02-12
期刊：
影响因子：
7.7
通讯作者：
Swartz, Kenton J.
中科院分区：
文献类型：
--
作者：
Jara-Oseguera, Andres;Bae, Chanhyung;Swartz, Kenton J.
感觉神经元中的TRPV 1通道是疼痛刺激和热的整合者，但它们如何整合不同的刺激和感觉温度仍然是一个谜。在这里，我们表明，外部钠离子稳定TRPV 1通道在一个封闭的状态，这样，删除外部离子导致通道激活。在研究潜在机制时，我们发现TRPV 1中的温度传感器分两步激活以促进开放，并且钠与细胞外位点的结合对温度传感器激活和孔的开放施加变构控制。狼蛛毒素的结合到外部孔也施加控制温度传感器激活，而香草素的结合通过在很大程度上影响开放/封闭平衡来影响温度敏感性。我们的结果揭示了外部孔在TRPV 1通道门控的变构控制中的基本作用，并为了解这些通道如何通过不同刺激进行调节提供了必要的限制。
TRPV1 channels in sensory neurons are integrators of painful stimuli and heat, yet how they integrate diverse stimuli and sense temperature remains elusive. Here, we show that external sodium ions stabilize the TRPV1 channel in a closed state, such that removing the external ion leads to channel activation. In studying the underlying mechanism, we find that the temperature sensors in TRPV1 activate in two steps to favor opening, and that the binding of sodium to an extracellular site exerts allosteric control over temperature-sensor activation and opening of the pore. The binding of a tarantula toxin to the external pore also exerts control over temperature-sensor activation, whereas binding of vanilloids influences temperature-sensitivity by largely affecting the open/closed equilibrium. Our results reveal a fundamental role of the external pore in the allosteric control of TRPV1 channel gating and provide essential constraints for understanding how these channels can be tuned by diverse stimuli.