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J. Biol. Chem., Vol. 282, Issue 39, 28669-28682, September 28, 2007

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Dynamic Integration of -Adrenergic and Cholinergic Signals in the Atria

ROLE OF G PROTEIN-REGULATED INWARDLY RECTIFYING K⁺ CHANNELS^*

From the Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834

Numerous heptahelical receptors use activation of heterotrimeric G proteins to convey a multitude of extracellular signals to appropriate effector molecules in the cell. Both high specificity and correct integration of these signals are required for reliable cell function. Yet the molecular machineries that allow each cell to merge information flowing across different receptors are not well understood. Here we demonstrate that G protein-regulated inwardly rectifying K⁺ (GIRK) channels can operate as dynamic integrators of -adrenergic and cholinergic signals in atrial myocytes. Acting at the last step of the cholinergic signaling cascade, these channels are activated by direct interactions with subunits of the inhibitory G proteins (G), and efficiently translate M₂ muscarinic acetylcholine receptor (M2R) activation into membrane hyperpolarization. The parallel activation of -adrenergic receptors imposed a distinctive "signature" on the function of M2R-activated GIRK1/4 channels, affecting both the probability of G binding to the channel and its desensitization. This modulation of channel function was correlated with a parallel depletion of G and protein phosphatase 1 from the oligomeric GIRK1 complexes. Such plasticity of the immediate GIRK signaling environment suggests that multireceptor integration involves large protein networks undergoing dynamic changes upon receptor activation.

Received for publication, May 3, 2007 , and in revised form, July 5, 2007.

^* This work was supported by Brody School of Medicine Faculty development grant (to T. I. N.) and funds from the Department of Pharmacology and Toxicology, East Carolina University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Brody Medical Sciences Bldg., Rm. 6S-11, Greenville, NC 27834-4354. Tel.: 252-744-2757; Fax: 252-744-3203; E-mail: ivanovanikolovat{at}ecu.edu.

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