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Title: Molecular Mechanism of Constitutive Endocytosis of Acid-Sensing Ion Channel 1a and Its Protective Function in Acidosis-Induced Neuronal Death
Author: Zeng, WZ ; Liu, DS ; Duan, B ; Song, XL ; Wang, X ; Wei, D ; Jiang, W ; Zhu, MX ; Li, Y ; Xu, TL
Source: JOURNAL OF NEUROSCIENCE
Issued Date: 2013
Volume: 33, Issue:16, Pages:7066-7078
Keyword: EPITHELIAL NA+ CHANNEL ; CLATHRIN-MEDIATED ENDOCYTOSIS ; COATED VESICLE FORMATION ; LIDDLES-SYNDROME ; NEURODEGENERATIVE DISEASES ; EXTRACELLULAR ACIDOSIS ; PAIN HYPERSENSITIVITY ; SURFACE EXPRESSION ; SODIUM-CHANNEL ; MUTATIONS
Subject: Neurosciences & Neurology
Corresponding Author: 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
English Abstract: 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.
Indexed Type: sci
Language: 英语
Content Type: 期刊论文
URI: http://ir.sibs.ac.cn/handle/331001/2523
Appears in Collections:神经所(总)_期刊论文

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Recommended Citation:
Zeng, WZ; Liu, DS; Duan, B; Song, XL; Wang, X; Wei, D; Jiang, W; Zhu, MX; Li, Y; Xu, TL.Molecular Mechanism of Constitutive Endocytosis of Acid-Sensing Ion Channel 1a and Its Protective Function in Acidosis-Induced Neuronal Death,JOURNAL OF NEUROSCIENCE,2013,33(16):7066-7078
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