TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain
TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain
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DOI：
10.1073/pnas.1715972115
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发表时间：
2018-02-13
影响因子：
11.1
通讯作者：
Morales-Lazaro, Sara L.
中科院分区：
文献类型：
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作者：
Ortiz-Renteria, Miguel;Juarez-Contreras, Rebeca;Morales-Lazaro, Sara L.
瞬时受体电位香草酸 1 (TRPV1) 离子通道在伤害感受器中表达，当被化学或热刺激激活时，它充当疼痛和瘙痒相关刺激的重要传感器。尽管 TRPV1 与调节其功能的蛋白质的相互作用先前已被探索过，但与其他哺乳动物 TRP 通道的情况一样，其分子伴侣的调节尚未阐明。在这里，我们展示了 TRPV1 与 Sigma 1 受体 (Sig-1R) 发生物理相互作用，Sigma 1 受体是一种结合黄体酮的分子伴侣，黄体酮是 Sig-1R 的拮抗剂，也是与疼痛调节相关的重要神经类固醇。黄体酮对 Sig-1R 的拮抗作用导致感觉神经元质膜中 TRPV1 表达下调，从而减少辣椒素诱导的伤害性反应。在用 Sig-1R 合成拮抗剂治疗的男性和黄体酮水平升高的怀孕女性中都观察到了这一点。这构成了一种先前未描述的机制，通过该机制可以调节 TRPV1 依赖性伤害感受和疼痛。
The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in nociceptors where, when activated by chemical or thermal stimuli, it functions as an important transducer of painful and itch-related stimuli. Although the interaction of TRPV1 with proteins that regulate its function has been previously explored, their modulation by chaperones has not been elucidated, as is the case for other mammalian TRP channels. Here we show that TRPV1 physically interacts with the Sigma 1 Receptor (Sig-1R), a chaperone that binds progesterone, an antagonist of Sig-1R and an important neurosteroid associated to the modulation of pain. Antagonism of Sig-1R by progesterone results in the down-regulation of TRPV1 expression in the plasma membrane of sensory neurons and, consequently, a decrease in capsaicin-induced nociceptive responses. This is observed both in males treated with a synthetic antagonist of Sig-1R and in pregnant females where progesterone levels are elevated. This constitutes a previously undescribed mechanism by which TRPV1-dependent nociception and pain can be regulated.