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 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.
Original language | English (US) |
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Pages (from-to) | 1350-1354 |
Number of pages | 5 |
Journal | Circulation research |
Volume | 107 |
Issue number | 11 |
DOIs | |
State | Published - Nov 26 2010 |
Keywords
- Cardiac
- G protein
- GIRK
- Knockout
- Muscarinic
- Regulators of G protein signaling