While the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) channel is a polymodal nociceptor for heat, capsaicin, and protons, the channel's responses to each of these stimuli are profoundly regulated by membrane potential, damping or even prohibiting its response at negative voltages and amplifying its response at positive voltages. Therefore, voltage sensitivity of TRPV1 is anticipated to play an important role in shaping pain responses. How voltage regulates TRPV1 activation remains unknown. Here, it is shown that voltage sensitivity does not originate from the S4 segment like classic voltage‐gated ion channels; instead, outer pore acidic residues directly partake in voltage‐sensitive activation, with their negative charges collectively constituting the observed gating charges. Outer pore gating‐charge movement is titratable by extracellular pH and is allosterically coupled to channel activation, likely by influencing the upper gate in the ion selectivity filter. Elucidating this unorthodox voltage‐gating process provides a mechanistic foundation for understanding TRPV1 polymodal gating and opens the door to novel approaches regulating channel activity for pain management.

中文翻译：

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TRPV1离子通道潜在的电压灵敏性的非常规机制

辣椒素受体瞬态受体电位香草酸1（TRPV1）通道是热量，辣椒素和质子的多峰伤害感受器，但通道对这些刺激的反应却受到膜电位的调节，抑制或什至禁止其在负电压下的反应。放大其在正电压下的响应。因此，预期TRPV1的电压敏感性在形成疼痛反应中起重要作用。电压如何调节TRPV1激活仍然未知。在这里，显示出电压灵敏度并非像传统的电压门控离子通道那样源自S4段。相反，外部孔隙酸性残基直接参与电压敏感活化，其负电荷共同构成观察到的门控电荷。外孔门控电荷的移动可通过细胞外pH进行滴定，并且与通道激活呈变构偶联，可能是通过影响离子选择性过滤器中的上浇口。阐明这种非常规的电压门控过程可为理解TRPV1多峰门控提供机制基础，并为调节疼痛活动的通道活性新方法打开了大门。