title: RGS6, a modulator of parasympathetic activation in heart.
abstract: BACKGROUND
  Parasympathetic regulation of heart rate is mediated by acetylcholine binding to G protein-coupled muscarinic M2 receptors, which activate heterotrimeric G(i/o) proteins to promote G protein-coupled inwardly rectifying K(+) (GIRK) channel activation. Regulator of G protein signaling (RGS) proteins, which function to inactivate G proteins, are indispensable for normal parasympathetic control of the heart. However, it is unclear which of the more than 20 known RGS proteins function to negatively regulate and thereby ensure normal parasympathetic control of the heart.
  
  
  OBJECTIVE
  To examine the specific contribution of RGS6 as an essential regulator of parasympathetic signaling in heart.
  
  
  RESULTS
  We developed RGS6 knockout mice to determine the functional impact of loss of RGS6 on parasympathetic regulation of cardiac automaticity. RGS6 exhibited a uniquely robust expression in the heart, particularly in sinoatrial and atrioventricular nodal regions. Loss of RGS6 provoked dramatically exaggerated bradycardia in response to carbachol in mice and isolated perfused hearts and significantly enhanced the effect of carbachol on inhibition of spontaneous action potential firing in sinoatrial node cells. Consistent with a role of RGS6 in G protein inactivation, RGS6-deficient atrial myocytes exhibited a significant reduction in the time course of acetylcholine-activated potassium current (I(K)(ACh)) activation and deactivation, as well as the extent of I(K)(ACh) desensitization.
  
  
  CONCLUSIONS
  RGS6 is a previously unrecognized, but essential, regulator of parasympathetic activation in heart, functioning to prevent parasympathetic override and severe bradycardia. These effects likely result from actions of RGS6 as a negative regulator of G protein activation of GIRK channels.
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Jianqi
authors.initials: J
authors.lastname: Yang
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Biswanath
authors.initials: B
authors.lastname: Maity
authors.forename: Zhan
authors.initials: Z
authors.lastname: Gao
authors.forename: Ramón A
authors.initials: RA
authors.lastname: Lorca
authors.forename: Hjalti
authors.initials: H
authors.lastname: Gudmundsson
authors.forename: Jingdong
authors.initials: J
authors.lastname: Li
authors.forename: Adele
authors.initials: A
authors.lastname: Stewart
authors.forename: Paari Dominic
authors.initials: PD
authors.lastname: Swaminathan
authors.forename: Stella-Rita
authors.initials: SR
authors.lastname: Ibeawuchi
authors.forename: Andrew
authors.initials: A
authors.lastname: Shepherd
authors.forename: Ching-Kang
authors.initials: CK
authors.lastname: Chen
authors.forename: William
authors.initials: W
authors.lastname: Kutschke
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Durga P
authors.initials: DP
authors.lastname: Mohapatra
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Rory A
authors.initials: RA
authors.lastname: Fisher
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001919:Bradycardia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000235:genetics / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017777:Parasympathetic Fibers, Postganglionic / Q000502:physiology*; D020710:RGS Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D043585:Receptor, Muscarinic M2 / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D012849:Sinoatrial Node / Q000502:physiology
chemical_list: D020710:RGS Proteins; D043585:Receptor, Muscarinic M2; C485692:Rgs6 protein, mouse