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J. Biol. Chem., Vol. 282, Issue 27, 19938-19947, July 6, 2007

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Signaling by a Non-dissociated Complex of G Protein β and Subunits Stimulated by a Receptor-independent Activator of G Protein Signaling, AGS8^*

Chujun Yuan, Motohiko Sato¹, Stephen M. Lanier², and Alan V. Smrcka^¶3

From the Departments of ^¶Pharmacology and Physiology and of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642 and the Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112

Accumulating evidence suggests that heterotrimeric G protein activation may not require G protein subunit dissociation. Results presented here provide evidence for a subunit dissociation-independent mechanism for G protein activation by a receptor-independent activator of G protein signaling, AGS8. AGS8 is a member of the AGS group III family of AGS proteins thought to activate G protein signaling primarily through interactions with Gβ subunits. Results are presented demonstrating that AGS8 binds to the effector and subunit binding "hot spot" on Gβ yet does not interfere with G subunit binding to Gβ or phospholipase C β2 activation. AGS8 stimulates activation of phospholipase C β2 by heterotrimeric Gβ and forms a quaternary complex with G_i1, Gβ₁₂, and phospholipase C β2. AGS8 rescued phospholipase C β binding and regulation by an inactive β subunit with a mutation in the hot spot (β₁(W99A)₂) that normally prevents binding and activation of phospholipase C β2. This demonstrates that, in the presence of AGS8, the hot spot is not used for Gβ interactions with phospholipase C β2. Mutation of an alternate binding site for phospholipase C β2 in the amino-terminal coiled-coil region of Gβ prevented AGS8-dependent phospholipase C binding and activation. These data implicate a mechanism for AGS8, and potentially other Gβ binding proteins, for directing Gβ signaling through alternative effector activation sites on Gβ in the absence of subunit dissociation.

Received for publication, January 16, 2007 , and in revised form, April 13, 2007.

^* This work was supported in part by National Institutes of Health Grants GM060286 and GM053536 (to A. V. S.) and NS24821 and MH55391 (to S. M. L.) and by an American Heart Association predoctoral fellowship grant (to C. Y.). 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 Present address: Cardiovascular Research Institute, Yokohama City University, School of Medicine, 3-9 Fukuura, Kanazawa-Ku, Yokohama 236-0004, Japan.

² Supported by the David R. Bethune/Lederle Laboratories Professorship in Pharmacology and the Research Scholar Award from Yamanouchi Pharmaceutical Company (now named Astellas Pharma Inc.). Present address: Dept. of Pharmacology, Colcock Hall, 2nd. Floor, P. O. Box 250002, Medical University of South Carolina, 179 Ashley Ave., Charleston, SC 29425.

³ To whom correspondence should be addressed: Dept. of Pharmacology & Physiology and Biochemistry & Biophysics, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642. Tel.: 585-275-0892; Fax: 585-273-2652; E-mail: Alan_Smrcka{at}urmc.rochester.edu.

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