globalchange  > 气候变化与战略
DOI: 10.1073/pnas.1912156116
论文题名:
Hearing loss mutations alter the functional properties of human P2X2 receptor channels through distinct mechanisms
作者: George B.; Swartz K.J.; Li M.
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2019
卷: 116, 期:45
起始页码: 22862
结束页码: 22871
语种: 英语
英文关键词: ATP ; Cochlea ; Deafness ; Purinergic
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
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.
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资源类型: 期刊论文
标识符: http://119.78.100.158/handle/2HF3EXSE/163615
Appears in Collections:气候变化与战略

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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

Recommended Citation:
George B.,Swartz K.J.,Li M.. Hearing loss mutations alter the functional properties of human P2X2 receptor channels through distinct mechanisms[J]. Proceedings of the National Academy of Sciences of the United States of America,2019-01-01,116(45)
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