Cyclic AMP-dependent and Epac-mediated activation of R-ras by G protein-coupled receptors leads to phospholipase D stimulation

Maider Lopez De Jesus, Matthias B. Stope, Paschal A. Oude Weernink, Yvonne Mahlke, Christof Boergermann, Viktoria N. Ananaba, Christian Rimmbach, Dieter Rosskopf, Martin C. Michel, Karl H. Jakobs, Martina Schmidt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

60 Citations (Scopus)


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 HEK293 cells stably expressing the M-3 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 M-3 mAChR is dependent on cyclic AMP formation but is independent of protein kinase A. Similar to the rather promiscuous M-3 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 M-3 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.

Original languageEnglish
Pages (from-to)21837-21847
Number of pages11
JournalThe Journal of Biological Chemistry
Issue number31
Publication statusPublished - 4-Aug-2006


  • RAP1
  • CAMP

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