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Title: Highly Conserved Salt Bridge Stabilizes Rigid Signal Patch at Extracellular Loop Critical for Surface Expression of Acid-sensing Ion Channels
Author: Yang, Yang ; Yu, Ye ; Cheng, Jin ; Liu, Yan ; Liu, Di-Shi ; Wang, Jin ; Zhu, Michael X. ; Wang, Rui ; Xu, Tian-Le(徐天乐)
Source: JOURNAL OF BIOLOGICAL CHEMISTRY
Issued Date: 2012
Volume: 287, Issue:18, Pages:14443-14455
Keyword: GATED CURRENT ; K+ CHANNEL ; PROTEIN ; DOMAIN ; ASIC3 ; CONTRIBUTES ; MECHANISMS ; ISCHEMIA ; NEURONS ; CATION
Subject: Biochemistry & Molecular Biology
Corresponding Author: Wang, R (reprint author), 222 Tian Shui S Rd, Lanzhou 730000, Peoples R China,wangrui@lzu.edu.cn
English Abstract: Acid-sensing ion channels (ASICs) are non-selective cation channels activated by extracellular acidosis associated with many physiological and pathological conditions. A detailed understanding of the mechanisms that govern cell surface expression of ASICs, therefore, is critical for better understanding of the cell signaling under acidosis conditions. In this study, we examined the role of a highly conserved salt bridge residing at the extracellular loop of rat ASIC3 (Asp(107)-Arg(153)) and human ASIC1a (Asp(107)-Arg(160)) channels. Comprehensive mutagenesis and electrophysiological recordings revealed that the salt bridge is essential for functional expression of ASICs in a pH sensing-independent manner. Surface biotinylation and immunolabeling of an extracellular epitope indicated that mutations, including even minor alterations, at the salt bridge impaired cell surface expression of ASICs. Molecular dynamics simulations, normal mode analysis, and further mutagenesis studies suggested a high stability and structural constrain of the salt bridge, which serves to separate an adjacent structurally rigid signal patch, important for surface expression, from a flexible gating domain. Thus, we provide the first evidence of structural requirement that involves a stabilizing salt bridge and an exposed rigid signal patch at the destined extracellular loop for normal surface expression of ASICs. These findings will allow evaluation of new strategies aimed at preventing excessive excitability and neuronal injury associated with tissue acidosis and ASIC activation.
Indexed Type: SCI
Language: 英语
Content Type: 期刊论文
URI: http://ir.sibs.ac.cn/handle/331001/1489
Appears in Collections:神经所(总)_期刊论文

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Yang, Yang; Yu, Ye; Cheng, Jin; Liu, Yan; Liu, Di-Shi; Wang, Jin; Zhu, Michael X.; Wang, Rui; Xu, Tian-Le.Highly Conserved Salt Bridge Stabilizes Rigid Signal Patch at Extracellular Loop Critical for Surface Expression of Acid-sensing Ion Channels,JOURNAL OF BIOLOGICAL CHEMISTRY,2012,287(18):14443-14455
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