The role of the MAGUK protein CASK for CaMKII activation in the heart

多功能钙/钙调蛋白依赖性蛋白激酶II(CaMKII)参与心力衰竭和心律失常的发生发展。我们以前的研究表明，兰诺丁受体肌浆网(SR)的钙释放通道功能紊乱，导致舒张期肌浆网钙泄漏和肌浆网钙含量降低。这再加上通过肌膜Na+通道的晚期Na+电流增加，可导致CaMKII依赖性心力衰竭和心律失常的发生。神经组织中描述的Maguk蛋白钙/钙调蛋白依赖的丝蛋白激酶(CASK)是CaMKII活性的调节者，同时具有重要的肌膜离子通道的结合域。到目前为止，CAASK与心脏中CaMKII的相关性还没有研究过，因此完全不清楚。在这项提议的初步实验中，我们可以证明CAASK在心脏中表达并与心肌CaMKII以及肌膜Na+通道NaV1.5相互作用。本项目的目标是研究CAASK对CaMKII活性、心律失常和心力衰竭发生的影响。主要问题是：1.心脏CaMKII依赖于CAMKII的调节机制是什么？CASK对CaMKII依赖的钠通道和Ryanodin受体的调节以及CaMKII依赖的心律失常和心力衰竭的发生有何影响？2.CAASK对兴奋性收缩偶联蛋白，特别是肌膜Na+通道和Ryanodin受体的作用是否是非CaMKII依赖的？3.上调CAASK是否可以作为一种治疗方法？我们相信，目前的项目可能会导致一种新的治疗心律失常和心力衰竭的方法，这可能具有临床意义。

The multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is involved in the development of heart failure and arrhythmias. Mechanistically we previously showed that the disturbed function of the Ca2+-release channel of the sarcoplasmic reticulum (SR), the ryanodin-receptor, leads to diastolic SR Ca2+-leak and a reduction of the SR Ca2+-content. This in addition to an increased late Na+-current through sarcolemmal Na+-channels (late INa) can results in the development of a CaMKII-dependent heart failure and arrhythmias.The MAGUK protein Ca2+/calmodulin-dependent serinprotein kinase (CASK) described in nerve tissue is a regulator of the CaMKII-activity and at the same time has binding domains for important sarcolemmal ion channels. The relevance of CASK for CaMKII in the heart has not been studied so far and therefore is completely unclear.In preliminary experiment for this proposal we could show that CASK in the heart is expressed and interacts both with the cardiac CaMKII as well as the sarcolemmal Na+-channel NaV1.5.Goal of the proposed project is to investigate the influence of CASK for CaMKII activity, arrhythmias and the development of heart failure. The main questions are:1. What is the mechanism of the CASK-dependent regulation of CaMKII in the heart and what is the influence of CASK on the CaMKII-dependent regulation of Na+-channels and the ryanodin-receptors, as well as CaMKII-dependent arrhythmias and heart failure development?2. Are the CaMKII-independent effects of CASK on protein of the excitationcontractioncoupling, especially the sarcolemmal Na+-channels and the ryanodin-receptor?3. Could an upregulation of CASK be a therapeutic approach?We believe that the current project could result in a novel approach to treat arrhythmias and heart failure which could be clinically relevant.