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

多功能Ca2+/钙调素依赖性蛋白激酶II （CaMKII）参与心力衰竭和心律失常的发展。在机制上，我们先前表明，肌浆网（SR）的Ca2+释放通道（红素受体）的功能紊乱，导致舒张期SR Ca2+泄漏和SR Ca2+含量降低。此外，通过肌上皮Na+通道（晚期Na）增加的晚期Na+电流可导致camkii依赖性心力衰竭和心律失常的发展。神经组织中描述的MAGUK蛋白Ca2+/钙调素依赖性丝氨酸蛋白激酶（CASK）是camkii活性的调节剂，同时具有重要的肌层离子通道的结合域。到目前为止，CASK与CaMKII在心脏中的相关性尚未得到研究，因此完全不清楚。在本提案的初步实验中，我们可以证明心脏中的CASK表达并与心脏CaMKII以及肌上皮Na+通道NaV1.5相互作用。该项目的目的是研究CASK对CaMKII活性、心律失常和心力衰竭发展的影响。主要问题是：1。1 .心脏中CaMKII依赖于CASK的调控机制是什么，CASK对CaMKII依赖于Na+通道和红素受体的调控，以及CaMKII依赖性心律失常和心力衰竭的发生有何影响？CASK对兴奋-收缩偶联蛋白，特别是肌上皮Na+通道和红素受体的影响是否独立于camkii ？上调CASK可以作为一种治疗方法吗？我们相信，目前的项目可能会导致一种治疗心律失常和心力衰竭的新方法，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.