Highly Conserved Salt Bridge Stabilizes Rigid Signal Patch at Extracellular Loop Critical for Surface Expression of Acid-sensing Ion Channels

CORC > 上海神经科学研究所 > 中国科学院上海生命科学研究院神经科学研究所 > 神经所(总)

	Highly Conserved Salt Bridge Stabilizes Rigid Signal Patch at Extracellular Loop Critical for Surface Expression of Acid-sensing Ion Channels
	Yang, Yang ; Yu, Ye ; Cheng, Jin ; Liu, Yan ; Liu, Di-Shi ; Wang, Jin ; Zhu, Michael X. ; Wang, Rui ; Xu, Tian-Le(徐天乐)
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2012
卷号	287 期号:18 页码:14443-14455
关键词	GATED CURRENT K+ CHANNEL PROTEIN DOMAIN ASIC3 CONTRIBUTES MECHANISMS ISCHEMIA NEURONS CATION
ISSN号	0021-9258
通讯作者	Wang, R (reprint author), 222 Tian Shui S Rd, Lanzhou 730000, Peoples R China,wangrui@lzu.edu.cn
英文摘要	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.
学科主题	Biochemistry & Molecular Biology
收录类别	SCI
资助信息	National Basic Research Program of China[2011CBA00408]; National Natural Science Foundation of China[91132303, 30830035, 31170787, 20932003]; Key National S&T Program "Major New Drug Development"[2012ZX09504001-003]; State Key Laboratory of Neuroscience
语种	英语
公开日期	2012-07-13
内容类型	期刊论文
源URL	[http://ir.sibs.ac.cn/handle/331001/1489]
专题	上海神经科学研究所_神经所(总)
推荐引用方式 GB/T 7714	Yang, Yang,Yu, Ye,Cheng, Jin,et al. Highly Conserved Salt Bridge Stabilizes Rigid Signal Patch at Extracellular Loop Critical for Surface Expression of Acid-sensing Ion Channels[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2012,287(18):14443-14455.
APA	Yang, Yang.,Yu, Ye.,Cheng, Jin.,Liu, Yan.,Liu, Di-Shi.,...&Xu, Tian-Le.(2012).Highly Conserved Salt Bridge Stabilizes Rigid Signal Patch at Extracellular Loop Critical for Surface Expression of Acid-sensing Ion Channels.JOURNAL OF BIOLOGICAL CHEMISTRY,287(18),14443-14455.
MLA	Yang, Yang,et al."Highly Conserved Salt Bridge Stabilizes Rigid Signal Patch at Extracellular Loop Critical for Surface Expression of Acid-sensing Ion Channels".JOURNAL OF BIOLOGICAL CHEMISTRY 287.18(2012):14443-14455.