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J. Biol. Chem., Vol. 279, Issue 6, 3906-3915, February 6, 2004

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Differential Contribution of GTPase Activation and Effector Antagonism to the Inhibitory Effect of RGS Proteins on G_q-mediated Signaling in Vivo^*

Thomas Anger, Wei Zhang, and Ulrike Mende

From the Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

RGS proteins act as negative regulators of G protein signaling by serving as GTPase-activating proteins (GAP) for subunits of heterotrimeric G proteins (G), thereby accelerating G protein inactivation. RGS proteins can also block G-mediated signal production by competing with downstream effectors for G binding. Little is known about the relative contribution of GAP and effector antagonism to the inhibitory effect of RGS proteins on G protein-mediated signaling. By comparing the inhibitory effect of RGS2, RGS3, RGS5, and RGS16 on G_q-mediated phospholipase C (PLC) activation under conditions where GTPase activation is possible versus nonexistent, we demonstrate that members of the R4 RGS subfamily differ significantly in their dependence on GTPase acceleration. COS-7 cells were transiently transfected with either muscarinic M₃ receptors, which couple to endogenous G_q protein and mediate a stimulatory effect of carbachol on PLC, or constitutively active G_q*, which is inert to GTP hydrolysis and activates PLC independent of receptor activation. In M₃-expressing cells, all of the RGS proteins significantly blunted the efficacy and potency of carbachol. In contrast, G_q* -induced PLC activation was inhibited by RGS2 and RGS3 but not RGS5 and RGS16. The observed differential effects were not due to changes in M₃, G_q/G_q*, PLC, or RGS expression, as shown by receptor binding assays and Western blots. We conclude that closely related R4 RGS family members differ in their mechanism of action. RGS5 and RGS16 appear to depend on G protein inactivation, whereas GAP-independent mechanisms (such as effector antagonism) are sufficient to mediate the inhibitory effect of RGS2 and RGS3.

Received for publication, August 27, 2003 , and in revised form, November 20, 2003.

^* This work was supported by Grant HL-52320 from the NHLBI, National Institutes of Health (to U. M.) and by American Heart Association Grant 9930032N (to U. M.). 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.

These authors contributed equally to this work.

To whom correspondence should be addressed: Brigham and Women's Hospital, Cardiovascular Division, Thorn Bldg. 1228A, 75 Francis St., Boston, MA 02115. Tel.: 617-732-7056; Fax: 617-732-5132; E-mail: umende{at}rics.bwh.harvard.edu.

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