气候变化领域集成服务门户(CCPortal): Functional cross-talk between phosphorylation and disease-causing mutations in the cardiac sodium channel Nav1.5

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DOI	10.1073/pnas.2025320118
	Functional cross-talk between phosphorylation and disease-causing mutations in the cardiac sodium channel Nav1.5
	Galleano I.; Harms H.; Choudhury K.; Khoo K.; Delemotte L.; Pless S.A.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:33
英文摘要	The voltage-gated sodium channel Nav1.5 initiates the cardiac action potential. Alterations of its activation and inactivation properties due to mutations can cause severe, life-threatening arrhythmias. Yet despite intensive research efforts, many functional aspects of this cardiac channel remain poorly understood. For instance, Nav1.5 undergoes extensive posttranslational modification in vivo, but the functional significance of these modifications is largely unexplored, especially under pathological conditions. This is because most conventional approaches are unable to insert metabolically stable posttranslational modification mimics, thus preventing a precise elucidation of the contribution by these modifications to channel function. Here, we overcome this limitation by using protein semisynthesis of Nav1.5 in live cells and carry out complementary molecular dynamics simulations. We introduce metabolically stable phosphorylation mimics on both wild-type (WT) and two pathogenic long-QT mutant channel backgrounds and decipher functional and pharmacological effects with unique precision. We elucidate the mechanism by which phosphorylation of Y1495 impairs steady-state inactivation in WT Nav1.5. Surprisingly, we find that while the Q1476R patient mutation does not affect inactivation on its own, it enhances the impairment of steady-state inactivation caused by phosphorylation of Y1495 through enhanced unbinding of the inactivation particle. We also show that both phosphorylation and patient mutations can impact Nav1.5 sensitivity toward the clinically used antiarrhythmic drugs quinidine and ranolazine, but not flecainide. The data highlight that functional effects of Nav1.5 phosphorylation can be dramatically amplified by patient mutations. Our work is thus likely to have implications for the interpretation of mutational phenotypes and the design of future drug regimens. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cardiac arrhythmia; Personalized medicine; Pharmacology; Protein engineering; Sodium channel inactivation
语种	英语
scopus关键词	flecainide; quinidine; ranolazine; sodium channel Nav1.5; SCN5A protein, human; sodium channel blocking agent; sodium channel Nav1.5; animal cell; Article; controlled study; drug design; gene mutation; heart muscle potential; heterologous expression; molecular dynamics; nonhuman; phenotype; protein expression; protein inactivation; protein modification; protein phosphorylation; protein synthesis; steady state; wild type; animal; drug effect; gene expression regulation; genetics; human; metabolism; molecular model; mutation; oocyte; patch clamp technique; phosphorylation; physiology; protein conformation; Xenopus laevis; Animals; Gene Expression Regulation; Humans; Models, Molecular; Molecular Dynamics Simulation; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Oocytes; Patch-Clamp Techniques; Phosphorylation; Protein Conformation; Sodium Channel Blockers; Xenopus laevis
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/251074
作者单位	Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, 2100, Denmark; Science for Life Laboratory, Department of Applied Physics, KTH Royal Institute of Technology, Solna, SE-171 65, Sweden
推荐引用方式 GB/T 7714	Galleano I.,Harms H.,Choudhury K.,et al. Functional cross-talk between phosphorylation and disease-causing mutations in the cardiac sodium channel Nav1.5[J],2021,118(33).
APA	Galleano I.,Harms H.,Choudhury K.,Khoo K.,Delemotte L.,&Pless S.A..(2021).Functional cross-talk between phosphorylation and disease-causing mutations in the cardiac sodium channel Nav1.5.Proceedings of the National Academy of Sciences of the United States of America,118(33).
MLA	Galleano I.,et al."Functional cross-talk between phosphorylation and disease-causing mutations in the cardiac sodium channel Nav1.5".Proceedings of the National Academy of Sciences of the United States of America 118.33(2021).