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

• Applicants: Professor Lars Maier; Professor Dr. Stefan Wagner
• Subject Area: Cardiology, Angiology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 348308761

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.

• DFG Programme: Research Grants