Rgs6 ablation in mice yielded profound delays in m2R-IKACh deactivation kinetics and mild resting bradycardia, demonstrating that the Rgs6/Gβ5 complex modulates parasympathetic heart rate regulation.
The Rgs6/Gβ5 complex is a critical modulator of parasympathetic heart rate regulation via m2R-IKACh signaling.
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.
Posokhova et al. (2010) studied this question. Rgs6 ablation (Rgs6-/-) vs. Wild-type mice was evaluated on m2R-IKACh deactivation kinetics and heart rate. Rgs6 ablation in mice yielded profound delays in m2R-IKACh deactivation kinetics and mild resting bradycardia, demonstrating that the Rgs6/Gβ5 complex modulates parasympathetic heart rate regulation.
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