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(Circulation Research. 2008;103:527.)
© 2008 American Heart Association, Inc.

Cellular Biology

RGS4 Regulates Parasympathetic Signaling and Heart Rate Control in the Sinoatrial Node

Carlo Cifelli^*, Robert A. Rose^*, Hangjun Zhang, Julia Voigtlaender-Bolz, Steffen-Sebastian Bolz, Peter H. Backx, Scott P. Heximer

From the Department of Physiology (C.C., R.A.R., H.Z., J.V.-B., S.-S.B., P.H.B., S.P.H.), Heart and Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto; and Department of Medicine (R.A.R., P.H.B.), University of Toronto, and Division of Cardiology, University Health Network, Toronto, Ontario, Canada.

Correspondence to Scott P. Heximer, Canada Research Chair in Cardiovascular Physiology, Heart and Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada. E-mail scott.heximer{at}utoronto.ca

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 M₂ muscarinic receptors and activation of G_i/o signaling. Although regulators of G protein signaling (RGS) proteins are potent inhibitors of G_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.

Key Words: RGS proteins • sinoatrial node • parasympathetic • GIRK channels

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