Journal article
RGS6, a Modulator of Parasympathetic Activation in Heart
Circulation research, Vol.107(11), pp.1345-1349
11/26/2010
DOI: 10.1161/CIRCRESAHA.110.224220
PMCID: PMC2997524
PMID: 20864673
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.
Details
- Title: Subtitle
- RGS6, a Modulator of Parasympathetic Activation in Heart
- Creators
- Jianqi Yang - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Jie Huang - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Biswanath Maity - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Zhan Gao - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Ramón A Lorca - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Hjalti Gudmundsson - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Jingdong Li - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Adele Stewart - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Paari Dominic Swaminathan - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Stella-Rita Ibeawuchi - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Andrew Shepherd - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Ching-Kang Chen - Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298-0614William Kutschke - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Peter J Mohler - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Durga P Mohapatra - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Mark E Anderson - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242Rory A Fisher - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.107(11), pp.1345-1349
- DOI
- 10.1161/CIRCRESAHA.110.224220
- PMID
- 20864673
- PMCID
- PMC2997524
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Language
- English
- Date published
- 11/26/2010
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040573002771
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