RGS6/Gβ5 complex accelerates IKACh 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 (m(2)Rs), pertussis toxin-sensitive (Gi/o) heterotrimeric G proteins, and the atrial potassium channel I(KACh). Molecular mechanisms regulating this critical signal transduction pathway are not fully understood. OBJECTIVE:To determine whether the G protein signaling regulator Rgs6/Gβ5 modulates m(2)R-I(KACh) signaling 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 of Rgs6 ablation were analyzed by whole-cell recordings in isolated cardiomyocytes and ECG telemetry. Loss of Rgs6 yielded profound delays in m(2)R-I(KACh) 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 m(2)R-I(KACh) signaling. CONCLUSIONS:The cardiac Rgs6/Gβ5 complex modulates the timing of parasympathetic influence on atrial myocytes and heart rate in mice.

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