RGS6, a modulator of parasympathetic activation in heart.

Abstract

RATIONALE:

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.

METHODS AND 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: Jianqi Yang, Jie Huang, Biswanath Maity, Zhan Gao, Ramón A Lorca, Hjalti Gudmundsson, Jingdong Li, Adele Stewart, Paari Dominic Swaminathan, Stella-Rita Ibeawuchi, Andrew Shepherd, Ching-Kang Chen, William Kutschke, Peter J Mohler, Durga P Mohapatra, Mark E Anderson, Rory A Fisher
• Journal: Circulation research (Circ Res) Vol. 107 Issue 11 Pg. 1345-9 (Nov 26 2010) ISSN: 1524-4571 [Electronic] United States
• PMID: 20864673 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• RGS Proteins
• Receptor, Muscarinic M2
• Rgs6 protein, mouse

Topics

• Action Potentials (genetics, physiology)
• Animals
• Bradycardia (genetics, metabolism, physiopathology)
• Cells, Cultured
• Heart (physiology)
• Heart Rate (genetics, physiology)
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• Parasympathetic Fibers, Postganglionic (physiology)
• RGS Proteins (deficiency, genetics, physiology)
• Receptor, Muscarinic M2 (physiology)
• Signal Transduction (genetics, physiology)
• Sinoatrial Node (physiology)