title: RGS4 regulates parasympathetic signaling and heart rate control in the sinoatrial node.
abstract: Heart rate is controlled by the opposing activities of sympathetic and parasympathetic inputs to pacemaker myocytes in the sinoatrial node (SAN). Parasympathetic activity on nodal myocytes is mediated by acetylcholine-dependent stimulation of M(2) muscarinic receptors and activation of Galpha(i/o) signaling. Although regulators of G protein signaling (RGS) proteins are potent inhibitors of Galpha(i/o) signaling in many tissues, the RGS protein(s) that regulate parasympathetic tone in the SAN are unknown. Our results demonstrate that RGS4 mRNA levels are higher in the SAN compared to right atrium. Conscious freely moving RGS4-null mice showed increased bradycardic responses to parasympathetic agonists compared to wild-type animals. Moreover, anesthetized RGS4-null mice had lower baseline heart rates and greater heart rate increases following atropine administration. Retrograde-perfused hearts from RGS4-null mice showed enhanced negative chronotropic responses to carbachol, whereas SAN myocytes showed greater sensitivity to carbachol-mediated reduction in the action potential firing rate. Finally, RGS4-null SAN cells showed decreased levels of G protein-coupled inward rectifying potassium (GIRK) channel desensitization and altered modulation of acetylcholine-sensitive potassium current (I(KACh)) kinetics following carbachol stimulation. Taken together, our studies establish that RGS4 plays an important role in regulating sinus rhythm by inhibiting parasympathetic signaling and I(KACh) activity.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Carlo
authors.initials: C
authors.lastname: Cifelli
authors.forename: Robert A
authors.initials: RA
authors.lastname: Rose
authors.forename: Hangjun
authors.initials: H
authors.lastname: Zhang
authors.forename: Julia
authors.initials: J
authors.lastname: Voigtlaender-Bolz
authors.forename: Steffen-Sebastian
authors.initials: SS
authors.lastname: Bolz
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.forename: Scott P
authors.initials: SP
authors.lastname: Heximer
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001919:Bradycardia / Q000503:physiopathology; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D007763:Lac Operon; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology; D010275:Parasympathetic Nervous System / Q000502:physiology*; D010276:Parasympatholytics / Q000494:pharmacology; D020710:RGS Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D012849:Sinoatrial Node / Q000294:innervation / Q000502:physiology*
chemical_list: D002316:Cardiotonic Agents; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D010276:Parasympatholytics; D020710:RGS Proteins; D012333:RNA, Messenger; C098799:RGS4 protein; D001285:Atropine; D002217:Carbachol