cPKC Regulation of Cardiac Potassium Channels

描述(申请人提供)：致命心律失常导致的心脏性猝死在美国每年造成约40万人死亡，约占充血性心力衰竭患者死亡率的一半，推测是室性心律失常所致。此外，药物引起的心律失常的风险因心力衰竭而增加近一倍。在人类心力衰竭和心力衰竭动物模型中，可以看到复极化钾通道Iks的减少，但这种Iks减少的机制在很大程度上是未知的。钙依赖的PKC异构体(CPKC)信号在心力衰竭时被强烈激活。在这里，我们提出了一个新的信号通路，在充血性心力衰竭的心律失常发生。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IKs减少，导致动作电位时程延长和钙超载，为心力衰竭和心律失常的进展奠定了基础。为了验证我们的假设，我们将：1)确定持续的PKC�激活是否通过KCNE 1(S102)的磷酸化抑制心肌细胞IKS膜的表达，从而导致APD值延长；2)开发特异性抑制IKS内化的KCNE1和KCNQ1多肽；3)确定CPKC介导的IKS内化在心力衰竭小鼠模型QT延长和心律失常倾向中的作用。通过执行这项建议中的工作，我们希望揭示心律失常发生的主要信号通路，特别是对于心力衰竭患者。我们希望我们的工作将揭开cPKC抑制剂作为一类新型抗心律失常药物的面纱。由于cPKC抑制剂也被认为影响钙处理，可能具有非心脏作用，我们希望开发新的iKS靶向药物原型，更具体地抑制QT延长和与心力衰竭相关的心律失常。

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.