Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons
Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons
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DOI：
10.1073/pnas.011404498
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发表时间：
2001-01-16
影响因子：
11.1
通讯作者：
McCleskey, EW
中科院分区：
文献类型：
--
作者：
Sutherland, SP;Benson, CJ;McCleskey, EW
心脏传入神经是介导心绞痛的感觉神经元，心绞痛是当心脏接受的血液供应不足以满足其代谢需求（缺血）时发生的疼痛。这些神经元显示出巨大的酸诱发去极化电流，并且它们响应于伴随心肌缺血的细胞外酸化而激发动作电位。在这里，我们表明，酸敏感离子通道3（ASIC 3），但没有其他已知的酸敏感离子通道，再现的功能特点的通道，在心脏传入的大酸诱发电流的基础。ASIC 3和天然通道都对pH特别敏感，与Ca 2+类似地相互作用，并在关闭、打开和脱敏状态之间快速门控。特别重要的是ASIC 3和天然通道在pH 7时打开的能力，这是心脏病发作前几分钟达到的值。陡峭的激活曲线表明，当四个质子结合时，通道打开。我们提出，ASIC 3，一个成员的简并蛋白通道（秀丽隐杆线虫）/上皮钠通道家族的离子通道，是传感器的心肌酸度，触发心脏疼痛，它可能是一个有用的药物治疗心绞痛的目标。
Cardiac afferents are sensory neurons that mediate angina, pain that occurs when the heart receives insufficient blood supply for its metabolic demand (ischemia). These neurons display enormous acid-evoked depolarizing currents, and they fire action potentials in response to extracellular acidification that accompanies myocardial ischemia. Here we show that acid-sensing ion channel 3 (ASIC3), but no other known acid-sensing ion channel, reproduces the functional features of the channel that underlies the large acid-evoked current in cardiac afferents. ASIC3 and the native channel are both especially sensitive to pH, interact similarly with Ca2+, and gate rapidly between closed, open, and desensitized states. Particularly important is the ability of ASIC3 and the native channel to open at pH 7, a value reached in the first few minutes of a heart attack. The steep activation curve suggests that the channel opens when four protons bind. We propose that ASIC3, a member of the degenerin channel (of Caenorhabditis elegans)/epithelial sodium channel family of ion channels, is the sensor of myocardial acidity that triggers cardiac pain, and that it might be a useful pharmaceutical target for treating angina.