cPKC Regulation of Cardiac Potassium Channels

描述（由申请方提供）：在美国，致死性心律失常导致的心源性猝死每年造成约400，000例死亡，约占充血性心力衰竭患者死亡率的一半，可能是由于室性心律失常所致。此外，药物诱导的心律失常的风险大约是心力衰竭的两倍。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IKs的减少，但这种IKs减少的机制在很大程度上是未知的。钙依赖性PKC亚型（cPKC）信号在心力衰竭中被强烈激活。在这里，我们提出了一个新的信号通路潜在的充血性心力衰竭的血管生成。我们认为，持续的cPKC激活通过cPKC-KCNE 1（S102）通路控制的通道内化导致IKs减少，导致动作电位时程（APD）和钙超载增加，为心力衰竭和心律失常的进展奠定基础。为了验证我们的假设，我们将：1）确定持续的PKC β激活是否通过KCNE 1（S102）磷酸化抑制心肌细胞中IKs膜表达，导致APD延长，2）开发基于KCNE 1和KCNQ 1的肽，特异性抑制IKs内化，3）确定cPKC介导的IKs内化对心力衰竭小鼠模型中QT延长和心律失常倾向的贡献。通过执行本提案中的工作，我们期望揭示心律失常发展的主要信号通路，特别是心力衰竭患者。我们希望我们的工作将揭示cPKC抑制剂作为一类新的抗肿瘤药物。由于cPKC抑制剂也被认为会影响钙的处理，并可能具有非心脏效应，因此我们希望开发新的IKs靶向药物原型，更特异地抑制与心力衰竭相关的QT间期延长和心律失常。

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.