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J. Biol. Chem., Vol. 277, Issue 16, 13827-13830, April 19, 2002

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Activator of G-protein Signaling 1 Blocks GIRK Channel Activation by a G-protein-coupled Receptor
APPARENT DISRUPTION OF RECEPTOR SIGNALING COMPLEXES^*

Aya Takesono, Mark W. Nowak, Mary Cismowski, Emir Duzic^§, and Stephen M. Lanier^¶

From the Department of Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425 and ^¶ Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112

The Ras-related protein, activator of G-protein signaling 1 (AGS1) or Dexras1, interacts with G_i/G_o and activates heterotrimeric G-protein signaling systems independent of a G-protein-coupled receptor (GPCR). As an initial approach to further define the cellular role of AGS1 in GPCR signaling, we determined the influence of AGS1 on the regulation of G-regulated inwardly rectifying K⁺ channel (GIRK) current (I_ACh) by M₂-muscarinic receptor (M₂-MR) in Xenopus oocytes. AGS1 expression inhibited receptor-mediated current activation by >80%. Mutation of a key residue (G31V) within the G₁ domain involved in nucleotide binding for Ras-related proteins eliminated the action of AGS1. The inhibition of I_ACh was not overcome by increasing concentrations of the muscarinic agonist acetylcholine but was progressively lost upon injection of increasing amounts of M₂-MR cRNA. These data suggest that AGS1 may antagonize GPCR signaling by altering the pool of heterotrimeric G-proteins available for receptor coupling and/or disruption of a preformed signaling complex. Such regulation would be of particular importance for those receptors that exist precoupled to heterotrimeric G-protein and for receptors operating within signaling complexes.

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