RGS6/Gβ5 complex accelerates I_KACh gating kinetics in atrial myocytes and modulates parasympathetic regulation of heart rate

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 channel IKACh. Molecular mechanisms regulating this critical signal transduction pathway are not fully understood. Objective: To determine whether the G protein signaling regulator Rgs6/β5 modulates m2R-IKACh signaling and cardiac physiology. Methods and Results: Cardiac expression of Rgs6, and its interaction with β5, was demonstrated by immunoblotting and immunoprecipitation. Rgs6^-/- mice were generated by gene targeting, and the cardiac effects of Rgs6 ablation were analyzed by whole-cell recordings in isolated cardiomyocytes and ECG telemetry. Loss of Rgs6 yielded profound delays in m2R-IKACh deactivation 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-IKACh signaling. Conclusions: The cardiac Rgs6/β5 complex modulates the timing of parasympathetic influence on atrial myocytes and heart rate in mice.