An Unorthodox Mechanism Underlying Voltage Sensitivity of TRPV1 Ion Channel.
An Unorthodox Mechanism Underlying Voltage Sensitivity of TRPV1 Ion Channel.
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DOI：
10.1002/advs.202000575
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Zheng J
中科院分区：
文献类型：
--
作者：
Yang F;Xu L;Lee BH;Xiao X;Yarov-Yarovoy V;Zheng J
虽然辣椒素受体瞬时受体电位香草酸1（TRPV 1）通道是热，辣椒素和质子的多模态伤害感受器，但通道对这些刺激的反应受到膜电位的深刻调节，在负电压下抑制甚至禁止其反应，并在正电压下放大其反应。因此，TRPV 1的电压敏感性预计在形成疼痛反应中起重要作用。电压如何调节TRPV 1激活仍然未知。在这里，它表明，电压敏感性不像经典的电压门控离子通道那样起源于S4段;相反，外孔酸性残基直接参与电压敏感性激活，它们的负电荷共同构成观察到的门控电荷。外孔门控-电荷运动可通过细胞外pH滴定，并可能通过影响离子选择性过滤器中的上门而与通道激活变构偶联。阐明这种非正统的电压门控过程为理解TRPV 1多模态门控提供了机制基础，并为调节通道活性以进行疼痛管理打开了大门。瞬时受体电位香草素1（TRPV 1）离子通道的电压敏感性不像经典的电压门控离子通道那样起源于S4段;相反，外孔酸性残基共同构成了观察到的门控电荷。外孔门控-电荷移动可通过细胞外pH滴定，并与通道激活变构偶联，可能通过影响离子选择性过滤器中的上门控。
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. Voltage sensitivity of transient receptor potential vanilloid 1 (TRPV1) ion channel does not originate from the S4 segment like classic voltage‐gated ion channels; instead, outer pore acidic residues collectively constitute 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.
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