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J. Biol. Chem., Vol. 281, Issue 31, 21837-21847, August 4, 2006

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Cyclic AMP-dependent and Epac-mediated Activation of R-Ras by G Protein-coupled Receptors Leads to Phospholipase D Stimulation^*

Maider López De Jesús¹², Matthias B. Stope¹³, Paschal A. Oude Weernink, Yvonne Mahlke, Christof Börgermann, Viktoria N. Ananaba, Christian Rimmbach⁴, Dieter Rosskopf⁴, Martin C. Michel, Karl H. Jakobs, and Martina Schmidt⁵

From the Institut für Pharmakologie, Universitätsklinikum Essen, 45122 Essen, Germany and the Department of Pharmacology and Pharmacotherapy, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

The activation of the Ras-related GTPase R-Ras, which has been implicated in the regulation of various cellular functions, by G protein-coupled receptors (GPCRs) was studied in HEK-293 cells stably expressing the M₃ muscarinic acetylcholine receptor (mAChR), which can couple to several types of heterotrimeric G proteins. Activation of the receptor induced a very rapid and transient activation of R-Ras. Studies with inhibitors and activators of various signaling pathways indicated that R-Ras activation by the M₃ mAChR is dependent on cyclic AMP formation but is independent of protein kinase A. Similar to the rather promiscuous M₃ mAChR, two typical G_s-coupled receptors also induced R-Ras activation. The receptor actions were mimicked by an Epac-specific cyclic AMP analog and suppressed by depletion of endogenous Epac1 by small interfering RNAs, as well as expression of a cyclic AMP binding-deficient Epac1 mutant, but not by expression of dominant negative Rap GTPases. In vitro studies demonstrated that Epac1 directly interacts with R-Ras and catalyzes GDP/GTP exchange at this GTPase. Finally, it is shown that the cyclic AMP- and Epac-activated R-Ras plays a major role in the M₃ mAChR-mediated stimulation of phospholipase D but not phospholipase C. Collectively, our data indicate that GPCRs rapidly activate R-Ras, that R-Ras activation by the GPCRs is apparently directly induced by cyclic AMP-regulated Epac proteins, and that activated R-Ras specifically controls GPCR-mediated phospholipase D stimulation.

Received for publication, May 1, 2006

^* This work was supported in part by the Deutsche Forschungsgemeinschaft, the Interne Forschungsförderung Essen, 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.

¹ Both authors contributed equally to this work.

² Recipient of a Basque Government Fellowship.

³ Present address: Institut für Molekulare Entwicklungs- und Zellphysiologie, Universität Karlsruhe, 76128 Karlsruhe, Germany.

⁴ Present address: Institut für Pharmakologie, Ernst-Moritz-Arndt-Universität Greifswald, 17487 Greifswald, Germany.

⁵ To whom correspondence should be addressed: Dept. of Molecular Pharmacology, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. Tel.: 31-50-363-3322; Fax: 31-50-363-6908; E-mail: m.schmidt{at}rug.nl.

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