瞬时受体电位锚蛋白1通道:1,4 - 二氢吡啶的新靶点。

TRPA1 channels: novel targets of 1,4-dihydropyridines.

作者信息

Fajardo Otto, Meseguer Victor, Belmonte Carlos, Viana Félix

机构信息

Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Alicante, Spain.

出版信息

Channels (Austin). 2008 Nov-Dec;2(6):429-38. doi: 10.4161/chan.2.6.7126. Epub 2008 Nov 3.

Abstract

Transient receptor potential type A1 (TRPA1) channels are cation permeable channels activated by irritant chemicals and pungent natural compounds. Their location in peptidergic sensory terminals innervating the skin and blood vessels makes them important effectors of vasodilator responses of neural origin. 1,4-dihydropyridines are a class of L-type calcium channel antagonists commonly used in the treatment of hypertension and ischemic heart disease. Here we show that four different 1,4-dihydropyridines (nifedipine, nimodipine, nicardipine and nitrendipine), and the structurally related L-type calcium channel agonist BayK8644, exert powerful excitatory effects on TRPA1 channels. The activation does not depend on elevated Ca2+ levels and cross-desensitizes with that produced by other TRPA1 agonists. The activation produced by nifedipine was reduced by camphor and the selective TRPA1 antagonist HC03001. In a subclass of mouse nociceptors expressing TRPA1 channels, assessed by responses to the TRPA1 agonist mustard oil, nifedipine also produced large elevations in Ca2+. These responses were fully abrogated in TRPA1(-/-) mice. These findings identify TRPA1 channels as a new molecular target for the 1,4-dihydropyridine class of calcium channel modulators.

摘要

瞬时受体电位A1型(TRPA1)通道是一类阳离子通透性通道,可被刺激性化学物质和辛辣天然化合物激活。它们位于支配皮肤和血管的肽能感觉神经末梢中,使其成为神经源性血管舒张反应的重要效应器。1,4-二氢吡啶是一类常用于治疗高血压和缺血性心脏病的L型钙通道拮抗剂。在此我们表明,四种不同的1,4-二氢吡啶(硝苯地平、尼莫地平、尼卡地平和尼群地平)以及结构相关的L型钙通道激动剂BayK8644对TRPA1通道具有强大的兴奋作用。这种激活不依赖于细胞外Ca2+水平的升高,并且与其他TRPA1激动剂产生的激活存在交叉脱敏现象。樟脑和选择性TRPA1拮抗剂HC03001可降低硝苯地平产生的激活作用。在一类通过对TRPA1激动剂芥子油的反应评估的表达TRPA1通道的小鼠伤害性感受器中,硝苯地平也使细胞内Ca2+浓度大幅升高。这些反应在TRPA1基因敲除小鼠中完全消失。这些发现确定TRPA1通道是1,4-二氢吡啶类钙通道调节剂的一个新分子靶点。

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