Molecular Mechanism of Constitutive Endocytosis of Acid-Sensing Ion Channel 1a and Its Protective Function in Acidosis-Induced Neuronal Death

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	Molecular Mechanism of Constitutive Endocytosis of Acid-Sensing Ion Channel 1a and Its Protective Function in Acidosis-Induced Neuronal Death
	Zeng, WZ ; Liu, DS ; Duan, B ; Song, XL ; Wang, X ; Wei, D ; Jiang, W ; Zhu, MX ; Li, Y ; Xu, TL
刊名	JOURNAL OF NEUROSCIENCE
	2013
卷号	33 期号:16 页码:7066-7078
关键词	EPITHELIAL NA+ CHANNEL CLATHRIN-MEDIATED ENDOCYTOSIS COATED VESICLE FORMATION LIDDLES-SYNDROME NEURODEGENERATIVE DISEASES EXTRACELLULAR ACIDOSIS PAIN HYPERSENSITIVITY SURFACE EXPRESSION SODIUM-CHANNEL MUTATIONS
ISSN号	0270-6474
通讯作者	Xu, TL (reprint author), Shanghai Jiao Tong Univ, Sch Med, Dept Anat & Embryol, Dept Biochem & Mol Cell Biol, Shanghai 200025, Peoples R China.,xu-happiness@shsmu.edu.cn
英文摘要	Acid-sensing ion channels (ASICs) are proton-gated cation channels widely expressed in the peripheral and CNSs, which critically contribute to a variety of pathophysiological conditions that involve tissue acidosis, such as ischemic stroke and epileptic seizures. However, the trafficking mechanisms of ASICs and the related proteins remain largely unknown. Here, we demonstrate that ASIC1a, the main ASIC subunit in the brain, undergoes constitutive endocytosis in a clathrin-and dynamin-dependentmannerin bothmousecortical neurons and heterologous cell cultures. The endocytosis of ASIC1a was inhibited by either the small molecular inhibitor tyrphostin A23 or knockdown of the core subunit of adaptor protein 2 (AP2) mu 2 using RNA interference, supporting a clathrin-dependent endocytosis of ASIC1a. In addition, the internalization of ASIC1a was blocked by dominant-negative dynamin1 mutation K44A and the small molecular inhibitor dynasore, suggesting that it is also dynamin-dependent. We show that the membrane-proximal residues (465)LCRRG(469) at the cytoplasmic C terminus of ASIC1a are critical for interaction with the endogenous adaptor protein complex and inhibition of ASIC1a internalization strongly exacerbated acidosis-induced death of cortical neurons from wild-type but not ASIC1a knock-out mice. Together, these results reveal the molecular mechanism of ASIC1a internalization and suggest the importance of endocytic pathway in functional regulation of ASIC1a channels as well as neuronal damages mediated by these channels during neurodegeneration.
学科主题	Neurosciences & Neurology
收录类别	SCI
资助信息	National Natural Science Foundation of China [31230028, 91213306, 91132303]; National Institutes of Health [RO1DK081654, RO1GM081658]; Shanghai Municipal Education Commission [J50201]; Shanghai Committee of Science and Technology [11DZ2260200]
语种	英语
公开日期	2013-06-04
内容类型	期刊论文
源URL	[http://ir.sibs.ac.cn/handle/331001/2523]
专题	上海神经科学研究所_神经所(总)
推荐引用方式 GB/T 7714	Zeng, WZ,Liu, DS,Duan, B,et al. Molecular Mechanism of Constitutive Endocytosis of Acid-Sensing Ion Channel 1a and Its Protective Function in Acidosis-Induced Neuronal Death[J]. JOURNAL OF NEUROSCIENCE,2013,33(16):7066-7078.
APA	Zeng, WZ.,Liu, DS.,Duan, B.,Song, XL.,Wang, X.,...&Xu, TL.(2013).Molecular Mechanism of Constitutive Endocytosis of Acid-Sensing Ion Channel 1a and Its Protective Function in Acidosis-Induced Neuronal Death.JOURNAL OF NEUROSCIENCE,33(16),7066-7078.
MLA	Zeng, WZ,et al."Molecular Mechanism of Constitutive Endocytosis of Acid-Sensing Ion Channel 1a and Its Protective Function in Acidosis-Induced Neuronal Death".JOURNAL OF NEUROSCIENCE 33.16(2013):7066-7078.