title: RGS6/Gβ5 complex accelerates IKACh gating kinetics in atrial myocytes and modulates parasympathetic regulation of heart rate.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Posokhova
authors.forename: Nicole
authors.initials: N
authors.lastname: Wydeven
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Allen
authors.forename: Kevin
authors.initials: K
authors.lastname: Wickman
authors.forename: Kirill A
authors.initials: KA
authors.lastname: Martemyanov
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology; D044387:GTP-Binding Protein beta Subunits / Q000502:physiology*; D057809:HEK293 Cells; D006325:Heart Atria / Q000166:cytology / Q000503:physiopathology; D006339:Heart Rate / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000502:physiology*; D017777:Parasympathetic Fibers, Postganglionic / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000502:physiology*; D020710:RGS Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D044387:GTP-Binding Protein beta Subunits; C094668:Gnb5 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D020710:RGS Proteins; C485692:Rgs6 protein, mouse; C059983:potassium channel protein I(sk)