TRP ion channels are modulated by phosphoinositide lipids, but the underlying structural mechanisms remain unclear. The capsaicin- and heat-activated receptor, TRPV1, has served as a model for deciphering lipid modulation, which is relevant to understanding how pro-algesic agents enhance channel activity in the setting of inflammatory pain. Identification of a pocket within the TRPV1 transmembrane core has provided initial clues as to how phosphoinositide lipids bind to and regulate the channel. Here we show that this regulatory pocket in rat TRPV1 can accommodate diverse lipid species, including the inflammatory lipid lysophosphatidic acid, whose actions are determined by their specific modes of binding. Furthermore, we show that an empty-pocket channel lacking an endogenous phosphoinositide lipid assumes an agonist-like state, even at low temperature, substantiating the concept that phosphoinositide lipids serve as negative TRPV1 modulators whose ejection from the binding pocket is a critical step toward activation by thermal or chemical stimuli.

TRP 离子通道受磷酸肌醇脂质调节，但潜在的结构机制仍不清楚。辣椒素和热激活受体 TRPV1 已成为破译脂质调节的模型，这与了解促痛剂如何增强炎性疼痛情况下的通道活性有关。 TRPV1 跨膜核心内口袋的鉴定为磷酸肌醇脂质如何结合和调节通道提供了初步线索。在这里，我们表明，大鼠 TRPV1 中的这个调节口袋可以容纳多种脂质种类，包括炎性脂质溶血磷脂酸，其作用由其特定的结合模式决定。此外，我们发现缺乏内源性磷酸肌醇脂质的空袋通道即使在低温下也呈现激动剂样状态，证实了磷酸肌醇脂质作为负TRPV1调节剂的概念，其从结合袋中弹出是激活的关键步骤通过热或化学刺激。