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

Circ Res. 2010 Nov 26;107(11):1350-4. doi: 10.1161/CIRCRESAHA.110.224212. Epub 2010 Sep 30.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Down-Regulation / genetics
  • Down-Regulation / physiology
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / physiology
  • GTP-Binding Protein beta Subunits / physiology*
  • HEK293 Cells
  • Heart Atria / cytology
  • Heart Atria / physiopathology
  • Heart Rate / genetics
  • Heart Rate / physiology*
  • Humans
  • Ion Channel Gating / genetics
  • Ion Channel Gating / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myocytes, Cardiac / physiology*
  • Parasympathetic Fibers, Postganglionic / physiology*
  • Potassium Channels, Voltage-Gated / antagonists & inhibitors
  • Potassium Channels, Voltage-Gated / physiology*
  • RGS Proteins / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Up-Regulation / genetics
  • Up-Regulation / physiology*


  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • GTP-Binding Protein beta Subunits
  • Gnb5 protein, mouse
  • Potassium Channels, Voltage-Gated
  • RGS Proteins
  • Rgs6 protein, mouse
  • potassium channel protein I(sk)