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J. Biol. Chem., Vol. 279, Issue 14, 13375-13382, April 2, 2004

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AGS3 and Signal Integration by G_s- and G_i-coupled Receptors

AGS3 BLOCKS THE SENSITIZATION OF ADENYLYL CYCLASE FOLLOWING PROLONGED STIMULATION OF A G_i-COUPLED RECEPTOR BY INFLUENCING PROCESSING OF G_i^*

Motohiko Sato, Thomas W. Gettys¶, and Stephen M. Lanier||

From the Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112 and the ^¶Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808

AGS3-LONG and AGS3-SHORT contain G-protein regulatory motifs that interact with and stabilize the GDP-bound conformation of G_i > G_o. AGS3 and related proteins may influence signal strength or duration as well as the adaptation of the signaling system associated with sustained stimulation. To address these issues, we determined the effect of AGS3 on the integration of stimulatory (G_s-mediated vasoactive intestinal peptide receptor) and inhibitory (G_i-mediated ₂-adrenergic receptor (₂-AR)) signals to adenylyl cyclase in Chinese hamster ovary cells. AGS3-SHORT and AGS3-LONG did not alter the VIP-induced increase in cAMP or the inhibitory effect of ₂-AR activation. System adaptation was addressed by determining the influence of AGS3 on the sensitization of adenylyl cyclase that occurs following prolonged activation of a G_i-coupled receptor. Incubation of cells with the ₂-AR agonist UK14304 (1 µM) for 18 h resulted in a 1.8-fold increase in the vasoactive intestinal peptide-induced activation of adenylyl cyclase, and this was associated with a decrease in membrane-associated G_i3. Both effects were blocked by AGS3-SHORT. AGS3-SHORT also decreased the rate of G_i3 decay. A mutant AGS3-SHORT incapable of binding G-protein was inactive. These data suggest that AGS3 and perhaps other G-protein regulatory motif-containing proteins increase the stability of G_i in the membrane, which influences the adaptation of the cell to prolonged activation of G_i-coupled receptors.

Received for publication, November 19, 2003 , and in revised form, January 12, 2004.

^* This work was supported in part by Grants NS24821 and MH55391 from the National Institutes of Health (to S. M. L.). 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.

Supported in part by the Mochida Memorial Foundation for Medical and Pharmaceutical Research.

^|| Supported by the David R. Bethune/Lederle Laboratories Professorship in Pharmacology and a Research Scholar Award from Yamanouchi Pharmaceutical Company, Ltd. To whom correspondence should be addressed: Dept. of Pharmacology, Louisiana State University Health Sciences Ctr., 1901 Perdido St., New Orleans, LA 70112. Tel.: 504-568-4740; E-mail: slanie{at}lsuhsc.edu.

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