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Regulation of the Cardiac Sodium Channel by Sumoylation

通过苏酰化调节心脏钠通道

基本信息

批准号：
10680501
负责人：
Kaikobad J. Irani
金额：
$ 63.67万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680501
关键词：
Acetylation Action Potentials Amino Acids Anti-Arrhythmia Agents Arginine Arrhythmia Biological Brugada syndrome CRISPR/Cas technology Calcium Cardiac Cardiac Myocytes Cardiomyopathies Data Deacetylase Defibrillators Dilated Cardiomyopathy Dimerization Disease Down-Regulation Electric Stimulation Electrocardiogram Enzymes Funding Genetic Diseases Genetic Polymorphism Heart Heart Atrium Heart failure Human Implantable Defibrillators Inherited Ion Channel Knock-in Knock-in Mouse Life Ligase Long QT Syndrome Lysine Maps Mediating Membrane Modification Molecular Mus Muscle Cells Mutate Mutation Myocardium Neonatal Neurons Optics Patients Phenotype Physiological Play Potassium Channel Predisposition Property Proteins Rattus Reagent Regional Perfusion Regulation Research Risk Role SUMO1 gene Secondary to Seizures Shock Single Nucleotide Polymorphism Sirtuins Sodium Sodium Channel Sudden Death Sumoylation Pathway Syndrome System Telemetry Testing Therapeutic Therapeutic Agents Transgenic Mice Ubiquitin Ubiquitination Ventricular Arrhythmia Viral Vector Work aorta constriction clinically relevant clinically significant cohort design gain of function heart electrical activity heart rhythm in vivo induced pluripotent stem cell loss of function novel overexpression pharmacologic sudden cardiac death tool trafficking ubiquitin ligase voltage

项目摘要

The cardiac Na+ channel SCN5A (Nav1.5) and the inward depolarizing Na+ current (INa) play a critical role in regulating the action potential of myocytes in the atrium, ventricle, and specialized conduction system. Mutations in SCN5A are associated with several arrhythmia phenotypes including long QT syndrome, Brugada syndrome, and dilated cardiomyopathy. In addition, loss of Na+ channel function is observed during heart failure, leading to conduction slowing and ventricular arrhythmias based on re-entrant mechanisms. Small Ubiquitin-like Modifiers (SUMOs), post-translationally modify lysine residues on proteins. Decrease in SUMOylation of cardiac calcium-handling proteins is associated with human heart failure. The significance of SUMOylation in regulating cardiac electrical activity is not known. Our preliminary data identifies a polymorphism in the SUMO1 gene that associates with appropriate defibrillator shocks in patients with heart failure, suggesting that SUMO1 modifies arrhythmia risk. Given our prior work demonstrating that acetylation of SCN5A on a lysine residue decreases cardiac sodium current, we now hypothesize that in addition to acetylation, SCN5A is post-translationally modified by SUMOylation, and SUMO-SCN5A is vital for the cardiac Na+ current and for normal electrical activity in the heart. This hypothesis is based on very novel preliminary data that SUMO1 modifies SCN5A and stimulates the Na+ current, whereas de-SUMOylation inhibits INa and precipitates cardiac arrhythmias in vivo. This application will explore in-depth the role of SUMOylation and de-SUMOylation on the cardiac Na+ current , characterizing their effect on channels properties, expression, ubiquitination, acetylation, trafficking, and interaction with its known partner Sirtuin1. The proposal will identify the lysine residues in SCN5A that are SUMOylated, and explore the importance of SUMOylation of these lysines on the cardiac Na+ current. It will develop and use state-of-the-art biological reagents, including a novel non-SUMOylatable Nav1.5 knockin mouse, cardiotropic viral vectors to SUMOylate and de-SUMOylate Nav1.5 in vivo, and transgenic mice overexpressing SUMO proteins. It will leverage the expertise of basic and mouse electrophysiologists, molecular biologists, and experts in cardiac SUMOylation. Using these reagents, and with the collective expertise of the investigative team, it will determine if SCN5A SUMOylation is altered in heart failure, and if cardiac SUMOylation modifies arrhythmic risk in failing and non-failing hearts. SUMO modification of SCN5A will identify a new mechanism for regulation of cardiac INa, and one that has potential clinical relevance in patients with heart failure. In doing so, it will open the door for using SUMO proteins as therapeutic agents in patients at risk for cardiac arrhythmias.

心脏Na+通道SCN 5A（Nav1.5）和内向去极化Na+电流（INa）在心肌细胞膜Na+通道的形成中起关键作用调节心房、心室和专门传导系统中肌细胞的动作电位。 SCN 5A的突变与几种心律失常表型相关，包括长QT综合征，布鲁加达综合征和扩张型心肌病。此外，在细胞凋亡过程中观察到Na+通道功能丧失。心力衰竭，导致传导减慢和基于折返机制的室性心律失常。小泛素样修饰剂（SUMO），后修饰蛋白质上的赖氨酸残基。减少心脏钙处理蛋白的SUMO化与人类心力衰竭有关。意义 SUMO化在调节心脏电活动中的作用尚不清楚。我们的初步数据表明， SUMO 1基因多态性与心脏病患者适当除颤器电击相关失败，表明SUMO 1改变心律失常风险。鉴于我们之前的工作证明乙酰化在赖氨酸残基上的SCN 5A降低了心脏钠电流，我们现在假设，除了由于SCN 5A的乙酰化，SCN 5A被SUMO化后修饰，SUMO-SCN 5A对心脏功能至关重要。 Na+电流和心脏中的正常电活动。这一假设是基于非常新颖的初步 SUMO 1修饰SCN 5A并刺激Na+电流，而去SUMO化抑制INa，在体内诱发心律失常。本申请将深入探讨SUMO化和去SUMO化对心脏Na+的作用，电流，表征它们对通道特性、表达、泛素化、乙酰化、运输，与已知的Sirtuin 1相互作用。该提案将确定SCN 5A中的赖氨酸残基， SUMO化，并探讨SUMO化这些赖氨酸对心脏Na+电流的重要性。它将开发和使用最先进的生物试剂，包括一种新型的不可SUMO化的Nav1.5敲入小鼠、体内SUMO化和去SUMO化Nav1.5的亲心病毒载体和转基因小鼠过表达SUMO蛋白。它将利用基础和小鼠电生理学家的专业知识，分子生物学家和心脏SUMO化的专家。使用这些试剂，研究小组的专业知识，它将确定是否SCN 5A SUMO化在心力衰竭中改变，心脏SUMO化改变了衰竭和非衰竭心脏中的心脏病风险。 SCN 5A的SUMO修饰将确定一种调节心脏INa的新机制，在心力衰竭患者中的潜在临床意义。这样做，它将打开大门，使用相扑蛋白质作为心律失常风险患者的治疗剂。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modulation of the cardiac sodium channel NaV1.5 peak and late currents by NAD+ precursors.

NAD 前体对心脏钠通道 NaV1.5 峰值电流和晚电流的调节。

DOI：
10.1016/j.yjmcc.2020.01.013
发表时间：
2020
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Matasic,DanielS;Yoon,Jin-Young;McLendon,JaredM;Mehdi,Haider;Schmidt,MarkS;Greiner,AlexanderM;Quinones,Pravda;Morgan,GinaM;Boudreau,RyanL;Irani,Kaikobad;Brenner,Charles;London,Barry
通讯作者：
London,Barry

The microRNA-204-5p inhibits APJ signalling and confers resistance to cardiac hypertrophy and dysfunction.

DOI：
10.1002/ctm2.693
发表时间：
2022-01
期刊：
Clinical and translational medicine
影响因子：
10.6
作者：
Gaddam RR;Kim YR;Jacobs JS;Yoon JY;Li Q;Cai A;Shankaiahgari H;London B;Irani K;Vikram A
通讯作者：
Vikram A

United We Stand; Divided We Fibrillate?

团结就是力量;