title: Essential role of the m2R-RGS6-IKACh pathway in controlling intrinsic heart rate variability.
abstract: Normal heart function requires generation of a regular rhythm by sinoatrial pacemaker cells and the alteration of this spontaneous heart rate by the autonomic input to match physiological demand. However, the molecular mechanisms that ensure consistent periodicity of cardiac contractions and fine tuning of this process by autonomic system are not completely understood. Here we examined the contribution of the m2R-I(KACh) intracellular signaling pathway, which mediates the negative chronotropic effect of parasympathetic stimulation, to the regulation of the cardiac pacemaking rhythm. Using isolated heart preparations and single-cell recordings we show that the m2R-I(KACh) signaling pathway controls the excitability and firing pattern of the sinoatrial cardiomyocytes and determines variability of cardiac rhythm in a manner independent from the autonomic input. Ablation of the major regulator of this pathway, Rgs6, in mice results in irregular cardiac rhythmicity and increases susceptibility to atrial fibrillation. We further identify several human subjects with variants in the RGS6 gene and show that the loss of function in RGS6 correlates with increased heart rate variability. These findings identify the essential role of the m2R-I(KACh) signaling pathway in the regulation of cardiac sinus rhythm and implicate RGS6 in arrhythmia pathogenesis.
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida, United States of America.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Posokhova
authors.forename: David
authors.initials: D
authors.lastname: Ng
authors.forename: Aaisha
authors.initials: A
authors.lastname: Opel
authors.forename: Ikuo
authors.initials: I
authors.lastname: Masuho
authors.forename: Andrew
authors.initials: A
authors.lastname: Tinker
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.forename: Kevin
authors.initials: K
authors.lastname: Wickman
authors.forename: Kirill A
authors.initials: KA
authors.lastname: Martemyanov
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology; D001341:Autonomic Nervous System / Q000502:physiology / Q000503:physiopathology; D004562:Electrocardiography; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D043585:Receptor, Muscarinic M2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012849:Sinoatrial Node / Q000166:cytology / Q000378:metabolism / Q000502:physiology
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D020710:RGS Proteins; D043585:Receptor, Muscarinic M2; C485692:Rgs6 protein, mouse; D000109:Acetylcholine