Novel gating and sensitizing mechanism of capsaicin receptor (TRPV1) - Tonic inhibitory regulation of extracellular sodium through the external protonation sites on TRPV1
Novel gating and sensitizing mechanism of capsaicin receptor (TRPV1) - Tonic inhibitory regulation of extracellular sodium through the external protonation sites on TRPV1
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DOI：
10.1074/jbc.m709377200
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发表时间：
2008-04-04
影响因子：
4.8
通讯作者：
Ito, Shigeo
中科院分区：
文献类型：
--
作者：
Ohta, Toshio;Imagawa, Toshiaki;Ito, Shigeo
瞬时受体电位V1（TRPV 1）是一种非选择性阳离子通道，表达于伤害感受器中，并被辣椒素激活。TRPV 1检测各种刺激，包括酸，热和内源性香草素，并作为疼痛感知的分子整合器。在此，我们证明了细胞外Na+（[Na+]（o））对TRPV 1功能的新的调节作用。在表达猪TRPV 1的人胚肾293细胞中，低[ Na+]（o）引起[Ca 2 +]（i）的增加，这被TRPV 1拮抗剂抑制，并促进对辣椒素、质子、热和内香草素的反应。[Na+]（o）的去除同时引起[Ca ~（2+）]（i）的增加和具有与辣椒素类似的反转电位的外向整流电流。两个酸性残基，赋予质子敏感性TRPV 1的中和导致低[Na+]（o）-诱导的反应减少。在原代培养的猪感觉神经元中，去除[Na+]（o）仅在对辣椒素有反应的细胞中产生[Ca 2 +]（i）增加和电流反应。低[Na+]（o）引起野生型小鼠感觉神经元[Ca 2 +]（i）增加，但TRPV 1缺失小鼠和表达人TRPV 1的人胚肾293细胞中未引起[Ca 2 +]（i）增加。目前的结果表明，[Na+]（o）负调控TRPV 1通道的门控和多模式敏化。[Na+]（o）围绕TRPV 1通道的孔形成环的细胞外侧上的几个质子敏感位点，可以作为抑制该通道在生理条件下的过度活性的制动器发挥重要作用。
Transient receptor potential V1 (TRPV1) is a nonselective cation channel expressed in nociceptors and activated by capsaicin. TRPV1 detects diverse stimuli, including acid, heat, and endogenous vanilloids, and functions as a molecular integrator of pain perception. Herein we demonstrate a novel regulatory role of extracellular Na+ ([Na+](o)) on TRPV1 function. In human embryonic kidney 293 cells expressing porcine TRPV1, low [ Na+](o) evoked increases of [Ca2+](i) that were suppressed by TRPV1 antagonists and facilitated responses to capsaicin, protons, heat, and an endovanilloid. [Na+](o) removal simultaneously elicited a [Ca2+](i) increase and outward-rectified current with a reversal potential similar to those of capsaicin. Neutralization of the two acidic residues which confer the proton sensitivity to TRPV1 resulted in a reduction of low [Na+](o)-induced responses. In primary culture of porcine sensory neurons, the removal of [Na+](o) produced a [Ca2+](i) increase and current responses only in the cells responding to capsaicin. Low [Na+](o) evoked a [Ca2+](i) increase in sensory neurons of wild type mice, but not TRPV1-null mice, and in human embryonic kidney 293 cells expressing human TRPV1. The present results suggest that [Na+](o) negatively regulates the gating and polymodal sensitization of the TRPV1 channel. [Na+](o) surrounding several proton-sensitive sites on the extracellular side of the pore-forming loop of the TRPV1 channel may play an important role as a brake to suppress the excessive activity of this channel under physiological conditions.