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(Circulation Research. 2006;98:659.)
© 2006 American Heart Association, Inc.

Cellular Biology

Endogenous RGS Proteins and G Subtypes Differentially Control Muscarinic and Adenosine-Mediated Chronotropic Effects

Ying Fu, Xinyan Huang, Huailing Zhong, Richard M. Mortensen, Louis G. D’Alecy, Richard R. Neubig

From the Departments of Pharmacology (Y.F., X.H., H.Z., R.M.M., R.R.N.), Molecular and Integrative Physiology (R.M.M., L.G.D’A.), and Surgery (Vascular) (L.G.D’A.), University of Michigan, Ann Arbor; and the Department of Surgery (L.G.D’A.), William Beaumont Hospital, Royal Oak, Mich.

Correspondence to R. R. Neubig, Department of Pharmacology, 1301 MSRB III, Ann Arbor, MI 48109. E-mail rneubig{at}umich.edu

Cardiac automaticity is controlled by G protein–coupled receptors, such as adrenergic, muscarinic, and adenosine receptors. The strength and duration of G protein signaling is attenuated by regulator of G protein signaling (RGS) proteins acting as GTPase-activating proteins for G subunits; however, little is known about the role of endogenous RGS proteins in cardiac function. We created point mutations in G subunits that disrupt G-RGS binding and introduced them into embryonic stem (ES) cells by homologous recombination. Spontaneously contacting cardiocytes derived from the ES cells were used to evaluate the role of endogenous RGS proteins in chronotropic regulation. The RGS-insensitive G_oG184S homozygous knock-in (G_oGS/GS) cells demonstrated enhanced adenosine A₁ and muscarinic M₂ receptor–mediated bradycardic responses. In contrast, G_i2GS/GS cells showed enhanced responses to M₂ but not A₁ receptors. Similarly M₂ but not A₁ bradycardic responses were dramatically enhanced in G_i2GS/GS mice. Blocking G protein–coupled inward rectifying K⁺ (GIRK) channels largely abolished the mutation-induced enhancement of the M₂ receptor–mediated response but had a minimal effect on A₁ responses. The G_s-dependent stimulation of beating rate by the ß₂ adrenergic receptor agonist procaterol was significantly attenuated in G_oGS/GS and nearly abolished in G_i2GS/GS cells because of enhanced signaling via a pertussis toxin sensitive mechanism. Thus, endogenous RGS proteins potently reduce the actions of G_i/o-linked receptors on cardiac automaticity. Furthermore, M₂ and A₁ receptors differentially use G_i2 and G_o and associated downstream effectors. Thus, alterations in RGS function may play a role in pathophysiological processes and RGS proteins could represent novel cardiovascular therapeutic targets.

Key Words: RGS • automaticity • adenosine receptor • ß₂ adrenergic receptor • muscarinic receptor

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