气候变化领域集成服务门户(CCPortal): An outer-pore gate modulates the pharmacology of the TMEM16A channel

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DOI	10.1073/pnas.2023572118
	An outer-pore gate modulates the pharmacology of the TMEM16A channel
	Dinsdale R.L.; Pipatpolkai T.; Agostinelli E.; Russell A.J.; Stansfeld P.J.; Tammaro P.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:34
英文摘要	TMEM16A Ca2+-activated chloride channels are involved in multiple cellular functions and are proposed targets for diseases such as hypertension, stroke, and cystic fibrosis. This therapeutic endeavor, however, suffers from paucity of selective and potent modulators. Here, exploiting a synthetic small molecule with a biphasic effect on the TMEM16A channel, anthracene-9-carboxylic acid (A9C), we shed light on sites of the channel amenable for pharmacological intervention. Mutant channels with the intracellular gate constitutively open were generated. These channels were entirely insensitive to extracellular A9C when intracellular Ca2+ was omitted. However, when physiological Ca2+ levels were reestablished, the mutants regained sensitivity to A9C. Thus, intracellular Ca2+ is mandatory for the channel response to an extracellular modulator. The underlying mechanism is a conformational change in the outer pore that enables A9C to enter the pore to reach its binding site. The explanation of this structural rearrangement highlights a critical site for pharmacological intervention and reveals an aspect of Ca2+ gating in the TMEM16A channel. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	CaCC; Calcium signalling; Pharmacology; TMEM16A
语种	英语
scopus关键词	9-anthroic acid; ANO1 protein, mouse; anoctamin 1; anthracene derivative; calcium; chloride; animal; drug effect; electrophysiology; electrostimulation; gene expression regulation; genetics; HEK293 cell line; human; metabolism; molecular dynamics; mouse; patch clamp technique; point mutation; Animals; Anoctamin-1; Anthracenes; Calcium; Chlorides; Electric Stimulation; Electrophysiological Phenomena; Gene Expression Regulation; HEK293 Cells; Humans; Mice; Molecular Dynamics Simulation; Network Pharmacology; Patch-Clamp Techniques; Point Mutation
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/251047
作者单位	Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, United Kingdom; Department of Chemistry, University of Oxford, Oxford, OX1 3TA, United Kingdom; Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, United Kingdom; Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, United Kingdom; School of Life Sciences, Department of Chemistry, University of Warwick, Coventry, CV4 7AL, United Kingdom
推荐引用方式 GB/T 7714	Dinsdale R.L.,Pipatpolkai T.,Agostinelli E.,et al. An outer-pore gate modulates the pharmacology of the TMEM16A channel[J],2021,118(34).
APA	Dinsdale R.L.,Pipatpolkai T.,Agostinelli E.,Russell A.J.,Stansfeld P.J.,&Tammaro P..(2021).An outer-pore gate modulates the pharmacology of the TMEM16A channel.Proceedings of the National Academy of Sciences of the United States of America,118(34).
MLA	Dinsdale R.L.,et al."An outer-pore gate modulates the pharmacology of the TMEM16A channel".Proceedings of the National Academy of Sciences of the United States of America 118.34(2021).