cPKC Regulation of Cardiac Potassium Channels

cPKC 对心脏钾通道的调节

• 批准号: 8720558
• 负责人: Coeli M. B. Lopes
• 金额: $ 37.61万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8720558
• 关键词: Action Potentials; Adenoviruses; Adult; Affect; American; Animal Model; Anti-Arrhythmia Agents; Arrhythmia; Calcium; Cardiac; Cardiac Myocytes; Cells; Cessation of life; Confocal Microscopy; Congestive Heart Failure; Cytoplasmic Tail; Data; Dependovirus; Development; Dominant-Negative Mutation; Drug Targeting; Echocardiography; Electrocardiogram; Functional disorder; Gene Expression; Heart; Heart failure; Human; Inherited; Ion Channel; Lead; Life; Measurement; Measures; Mediating; Membrane; Membrane Proteins; Modeling; Molecular; Mus; Mutagenesis; Mutation; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phosphorylation; Potassium; Potassium Channel; Protein Isoforms; Rattus; Regulation; Risk; Rodent Model; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Sorting - Cell Movement; Staging; Sudden Death; Testing; Time; Ventricular Arrhythmia; Work; base; gain of function; hemodynamics; in vivo; inhibitor/antagonist; insight; loss of function; mortality; mouse model; mutant; new therapeutic target; novel; overexpression; prenylation; pressure; protein function; prototype; public health relevance; sudden cardiac death; tool

DESCRIPTION (provided by applicant): Sudden cardiac death due to fatal arrhythmias is responsible for approximately 400,000 deaths annually in the US and is responsible for approximately half of the mortality in patients with congestive heart failure, presumably due to ventricular arrhythmias. In addition, the risk of drug induced arrhythmias is approximately doubled by heart failure. Decrease in the repolarizing potassium channel IKs is seen in human failing hearts and animal models of heart failure but the mechanism for this IKs reduction is largely unknown. Calcium dependent PKC isoforms (cPKC) signaling is strongly activated in heart failure. Here we propose a novel signaling pathway underlying arrhythmogenesis in congestive heart failure. We propose that sustained cPKC activation leads to decrease in IKs via the channel internalization controlled by cPKC-KCNE1(S102) pathway underlying an increase in action potential duration (APD) and calcium overload, setting the stage for progression of heart failure and cardiac arrhythmias. To test our hypothesis we will: 1) determine whether sustained PKC¿-activation inhibits IKs membrane expression via KCNE1(S102) phosphorylation in cardiomyocytes leading to APD prolongation, 2) develop KCNE1 and KCNQ1 based peptides that specifically inhibit IKs internalization, 3) determine the contribution of cPKC mediated IKs internalization to QT prolongation and arrhythmia propensity in a heart failure mouse model. By performing the work in this proposal we expect to uncover a major signaling pathway underlying the development of cardiac arrhythmias, in particular for heart failure patients. We expect our work will unveil cPKC inhibitors as a novel class of antiarrhythmic drugs. Because cPKC inhibitors are also thought to affect calcium handling and may have non-cardiac effects, we expect to develop new IKs-target drug prototypes that more specifically inhibit QT prolongation and arrhythmias associated with heart failure.

描述（由申请人提供）：在美国，致命性心律失常导致的心脏性猝死每年导致约 400,000 人死亡，并且约占充血性心力衰竭患者死亡率的一半（推测是由于室性心律失常所致）。此外，心力衰竭导致药物引起心律失常的风险大约增加一倍。在人类衰竭心脏和心力衰竭动物模型中观察到复极化钾通道 IK 减少，但这种 IK 减少的机制很大程度上未知。钙依赖性 PKC 亚型 (cPKC) 信号在心力衰竭中被强烈激活。在这里，我们提出了一种与充血性心力衰竭心律失常发生相关的新信号通路。我们认为，持续的 cPKC 激活通过 cPKC-KCNE1(S102) 通路控制的通道内化导致 IK 减少，导致动作电位持续时间 (APD) 增加和钙超载，从而为心力衰竭和心律失常的进展奠定基础。为了检验我们的假设，我们将：1) 确定持续的 PKC¿ 激活是否通过心肌细胞中的 KCNE1(S102) 磷酸化抑制 IK 膜表达，导致 APD 延长，2) 开发基于 KCNE1 和 KCNQ1 的肽，特异性抑制 IK 内化，3) 确定 cPKC 介导的 IK 内化对 QT 延长的贡献，以及 心力衰竭小鼠模型中的心律失常倾向。通过执行本提案中的工作，我们期望揭示心律失常发展背后的主要信号传导途径，特别是对于心力衰竭患者。我们预计我们的工作将揭示 cPKC 抑制剂作为一类新型抗心律失常药物。由于 cPKC 抑制剂也被认为会影响钙处理，并可能具有非心脏作用，因此我们期望开发新的 IK 靶向药物原型，更具体地抑制与心力衰竭相关的 QT 延长和心律失常。