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靶向酸敏感离子通道的神经保护：酸毒性损伤机制的重新审视

王晶晶, 徐天乐^*

上海交通大学医学院基础医学院解剖学与组织胚胎学系，脑科学协同创新中心，上海 200025

摘要

生理水平的质子在生物体内分布广泛，具有重要的生理功能。在特定的病理条件下，正常的酸碱平衡被破坏，导致质子大量生成和累积，产生对机体有害的酸毒(acidotoxicity)。组织酸化是多种神经系统疾病(如缺血性中风、多发性硬化症以及亨廷顿舞蹈症等)的共同病理特征，也是致这些疾病神经损伤的原因之一。质子可直接激活酸敏感离子通道(acid-sensing ion channel, ASIC)，介导组织酸化相关的生理和病理功能，例如，缺血性神经损伤。一直以来，ASIC引起酸毒性神经损伤被认为主要依赖于通道介导的细胞内钙离子升高。然而，本研究组新近的研究表明ASIC1a亚型通道能够通过激活受体相互作用蛋白1 (receptor-interacting protein 1, RIP1)，介导不依赖于通道离子通透功能的细胞程序性坏死。另外，亚细胞定位研究发现，除了在神经元膜表面，ASIC1a还可以定位在线粒体内膜上，通过调控线粒体通透性转变(mitochondrial permeability transition, MPT)过程，在缺血性神经损伤中发挥重要作用。这些进展使人们对于ASIC介导神经元死亡的机制有了新的认识。

关键词： 酸敏感离子通道1a; 酸毒; 神经保护; 缺血性中风

分类号：xu-happiness@shsmu.edu.cn

Acid-sensing ion channels as a target for neuroprotection: acidotoxicity revisited

WANG Jing-Jing, XU Tian-Le^*

Department of Anatomy, Histology and Embryology, Institute of Medical Sciences, Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University School of Medicine, Shanghai 200025 , China

Abstract

Protons are widespread in cells and serve a variety of important functions. In certain pathological conditions, acid-base balance was disrupted and therefore excessive protons were generated and accumulated, which is termed acidosis and proved toxic to the organism. In the nervous system, it has been reported that acidosis was a common phenomenon and contributed to neuronal injury in various kinds of neurological diseases, such as ischemic stroke, multiple sclerosis and Huntington’s disease. Acid-sensing ion channels (ASICs) is the key receptor of protons and mediates acidosis-induced neuronal injury, but the underlying mechanism remains unclear. Traditionally, Ca2+ influx through homomeric ASIC1a channels has been considered to be the main cause of acidotoxicity. Recent research showed that extracellular protons trigger a novel form of necroptosis in neurons via ASIC1a-mediated serine/threonine kinase receptor interaction protein 1 (RIP1) activation, independent of ion-conducting function of ASIC1a. In addition, ASIC1a was found in mitochondria and regulated mitochondrial permeability transition-dependent neuronal death. In this article, we will review the recent progresses on the mechanisms underlying ASIC-mediated neuronal death and discuss ASIC modulators involved in this process.

Key words: ASIC1a; acidotoxicity; neuroprotection; ischemic stroke

收稿日期：2016-05-25　　录用日期：2016-06-15

通讯作者：徐天乐　　E-mail: xu-happiness@shsmu.edu.cn

引用本文：

王晶晶, 徐天乐. 靶向酸敏感离子通道的神经保护：酸毒性损伤机制的重新审视[J]. 生理学报 2016; 68 (4): 403-413.

WANG Jing-Jing, XU Tian-Le. Acid-sensing ion channels as a target for neuroprotection: acidotoxicity revisited. Acta Physiol Sin 2016; 68 (4): 403-413 (in Chinese with English abstract).