气候变化领域集成服务门户(CCPortal): Hearing loss mutations alter the functional properties of human P2X2 receptor channels through distinct mechanisms

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DOI	10.1073/pnas.1912156116
	Hearing loss mutations alter the functional properties of human P2X2 receptor channels through distinct mechanisms
	George B.; Swartz K.J.; Li M.
发表日期	2019
ISSN	0027-8424
起始页码	22862
结束页码	22871
卷号	116 期号:45
英文摘要	Activation of P2X2 receptor channels by extracellular ATP is thought to play important roles in cochlear adaptation to elevated sound levels and protection from overstimulation. Each subunit of a trimeric P2X2 receptor is composed of intracellular N and C termini, a large extracellular domain containing the ATP binding site and 2 transmembrane helices (TM1 and TM2) that form a cation permeable pore. Whole-exome sequencing and linkage analysis have identified 3 hP2X2 receptor mutations (V60L, D273Y, and G353R) that cause dominantly inherited progressive sensorineural hearing loss (DFNA41). Available structures of related P2X receptors suggest that these 3 mutations localize to TM1 (V60L), TM2 (G353R), or the β-sheet linking the TMs to the extracellular ATP binding sites (D273Y). Previous studies have concluded that the V60L and G353R mutants are nonfunctional, whereas the D273Y mutant has yet to be studied. Here, we demonstrate that both V60L and G353R mutations do form functional channels, whereas the D273Y mutation prevents the expression of functional channels on the cell membrane. Our results show that the V60L mutant forms constitutively active channels that are insensitive to ATP or the antagonist suramin, suggesting uncoupling of the pore and the ligand binding domains. In contrast, the G353R mutant can be activated by ATP but exhibits alterations in sensitivity to ATP, inward rectification, and ion selectivity. Collectively, our results demonstrate that the loss of functional P2X2 receptors or distinct alterations of its functional properties lead to noise-induced hearing loss, highlighting the importance of these channels in preserving hearing. © 2019 National Academy of Sciences. All rights reserved.
英文关键词	ATP; Cochlea; Deafness; Purinergic
语种	英语
scopus关键词	adenosine triphosphate; ion channel; purinergic P2X2 receptor; suramin; Article; biophysics; cell membrane; clinical article; cochlea; controlled study; EC50; enzyme activation; gene mutation; hearing impairment; HEK293 cell line; human; mathematical model; perception deafness; priority journal; protein expression; protein function; protein modification; whole exome sequencing; wild type
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/160422
作者单位	George, B., Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-3701, United States; Swartz, K.J., Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-3701, United States; Li, M., Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-3701, United States
推荐引用方式 GB/T 7714	George B.,Swartz K.J.,Li M.. Hearing loss mutations alter the functional properties of human P2X2 receptor channels through distinct mechanisms[J],2019,116(45).
APA	George B.,Swartz K.J.,&Li M..(2019).Hearing loss mutations alter the functional properties of human P2X2 receptor channels through distinct mechanisms.Proceedings of the National Academy of Sciences of the United States of America,116(45).
MLA	George B.,et al."Hearing loss mutations alter the functional properties of human P2X2 receptor channels through distinct mechanisms".Proceedings of the National Academy of Sciences of the United States of America 116.45(2019).