RGS6/Gβ5 Complex AcceleratesIKAChGating Kinetics in Atrial Myocytes and Modulates Parasympathetic Regulation of Heart Rate

Abstract

Rationale:The parasympathetic reduction in heart rate involves the sequential activation of m2 muscarinic cholinergic receptors (m2Rs), pertussis toxin–sensitive (Gi/o) heterotrimeric G proteins, and the atrial potassium channelIKACh. Molecular mechanisms regulating this critical signal transduction pathway are not fully understood.Objective:To determine whether the G protein signaling regulator Rgs6/Gβ5 modulates m2R-IKAChsignaling and cardiac physiology.Methods and Results:Cardiac expression of Rgs6, and its interaction with Gβ5, was demonstrated by immunoblotting and immunoprecipitation.Rgs6−/−mice were generated by gene targeting, and the cardiac effects ofRgs6ablation were analyzed by whole-cell recordings in isolated cardiomyocytes and ECG telemetry. Loss of Rgs6 yielded profound delays in m2R-IKAChdeactivation kinetics in both neonatal atrial myocytes and adult sinoatrial nodal cells.Rgs6−/−mice exhibited mild resting bradycardia and altered heart rate responses to pharmacological manipulations that were consistent with enhanced m2R-IKAChsignaling.Conclusions:The cardiac Rgs6/Gβ5 complex modulates the timing of parasympathetic influence on atrial myocytes and heart rate in mice.