VAP-Proteine sind wesentliche Bestandteile nativer HCN2-Kanalkomplexe und regulieren die Funktion deskardialen If -Schrittmacherstroms

HCN channels have been described to contribute to the pacemaking mechanism of excitable cells of the heart muscle and in neurons of the central nervous system. HCN channels control the action potential fire frequency in these cells. They are open within hyperpolarization and accordingly drive a depolarization of the membrane. In the here presented thesis the vesicle associated membrane associated protein B (VAPB) was identified as an endogenous interaction partner with modulatory effect on heart rate and neuronal distribution of the HCN2. VAPB has a time- independent but concentration-dependent impact on the current amplitude of HCN2. However the activation kinetics and the gating of the channel is not altered by a co-expression. Patch Clamp experiments of the spontaneously active heart muscle cell line HL-1 showed a prolonged diastolic depolarization and action potential duration (APD50) under knock-down conditions via shRNA. Furthermore examining VAPB knock-out mice revealed a cardiac phenotype particularly a bradycardia.