RGS6, a modulator of parasympathetic activation in heart.
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.
Yang
Jianqi
J
Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Huang
Jie
J
Maity
Biswanath
B
Gao
Zhan
Z
Lorca
Ramón A
RA
Gudmundsson
Hjalti
H
Li
Jingdong
J
Stewart
Adele
A
Swaminathan
Paari Dominic
PD
Ibeawuchi
Stella-Rita
SR
Shepherd
Andrew
A
Chen
Ching-Kang
CK
Kutschke
William
W
Mohler
Peter J
PJ
Mohapatra
Durga P
DP
Anderson
Mark E
ME
Fisher
Rory A
RA
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
D020710:RGS Proteins; D043585:Receptor, Muscarinic M2; C485692:Rgs6 protein, mouse