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J. Biol. Chem., Vol. 278, Issue 31, 28743-28749, August 1, 2003

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Receptor-dependent RhoA Activation in G₁₂/G₁₃-deficient Cells

GENETIC EVIDENCE FOR AN INVOLVEMENT OF G_q/G₁₁^*

Stephan Vogt , Robert Grosse , Günter Schultz  and Stefan Offermanns  ¶

From the Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany and the Institute of Pharmacology, Free University Berlin, Thielallee 69-73, 14195 Berlin, Germany

The small GTPase RhoA is involved in the regulation of various cellular functions like the remodeling of the actin cytoskeleton and the induction of transcriptional activity. G-protein-coupled receptors (GPCRs), which are able to activate Gq/G₁₁ and G₁₂/G₁₃ are major upstream regulators of RhoA activity, and G₁₂/G₁₃ have been shown to couple GPCRs to the activation of Rho by regulating the activity of a subfamily of RhoGEF proteins. However, the possible contribution of G_q/G₁₁ to the regulation of RhoA activity via GPCRs is controversial. We have used a genetic approach to study the role of heterotrimeric G-proteins in the activation of RhoA via endogenous GPCRs. In pertussis toxin-treated G₁₂/G₁₃-deficient as well as in G_q/G₁₁-deficient mouse embryonic fibroblasts (MEFs), in which coupling of receptors is restricted to G_q/G₁₁ and G₁₂/G₁₃, respectively, receptor activation results in Rho activation. Rho activation induced by receptor agonists via G_q/G₁₁ occurs with lower potency than Rho activation via G₁₂/G₁₃. Activation of RhoA via G_q/G₁₁ is not affected by the phospholipase-C blocker U73122 or the Ca²⁺-chelator BAPTA, but can be blocked by a dominant-negative mutant of the RhoGEF protein LARG. Our data clearly show that G₁₂/G₁₃ as well as G_q/G₁₁ alone can couple GPCRs to the rapid activation of RhoA. G_q/G₁₁-mediated RhoA activation occurs independently of phospholipase C- and appears to involve LARG.

Received for publication, May 1, 2003 , and in revised form, May 19, 2003.

^* This work was supported by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie. 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.

^¶ To whom correspondence should be addressed: Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Tel.: 49-6221-54-8247; Fax: 49-6221-54-8549; E-mail: Stefan.Offermanns{at}urz.uni-heidelberg.de.

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