DESCRIPTION (provided by applicant): Purkinje cell protein 4, PCP4, was recently identified as a regulator of cardiac Purkinje cell excitability and cardiac rhythmicity through effects in bot the His-Purkinje network of the specialized ventricular conduction system as well the autonomic nervous system. PCP4 knockout mice demonstrate ventricular arrhythmias as well as autonomically mediated sudden cardiac death. PCP4's effect on the Purkinje cells were dependent on CaMKII, and included increased calcium current density, a propensity for intracellular calcium accumulation, and spontaneous calcium release events. The proposal aims are to determine which phenotypic effects of PCP4 loss of function are attributable to cell autonomous effects within cardiac Purkinje cells versus those attributable to the autonomic nervous system. This will be accomplished through cell-type specific gene deletion. We also propose to determine the role of PCP4 as a genetic modifier of arrhythmic susceptibility, by characterizing the effects of loss of function of PCP4 in mouse models of inherited arrhythmic syndromes, as well as by screening for sequence variants within the PCP4 gene in human patients with inherited arrhythmic conditions.