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J. Biol. Chem., Vol. 283, Issue 45, 30754-30765, November 7, 2008

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RhoA GTPase and F-actin Dynamically Regulate the Permeability of Cx43-made Channels in Rat Cardiac Myocytes^*

Mickaël Derangeon, Nicolas Bourmeyster, Isabelle Plaisance, Caroline Pinet-Charvet, Qian Chen, Fabien Duthe, Michel R. Popoff, Denis Sarrouilhe, and Jean-Claude Hervé¹

From the Institut de Physiologie et Biologie Cellulaires, Université de Poitiers, CNRS 6187, 40 avenue du recteur Pineau, F-86022 Poitiers and Unité des Bactéries Anaérobies et Toxines, Institut Pasteur, 25–28 rue du Dr Roux, F-75724 Paris Cédex 15, France

Gap junctions are clusters of transmembrane channels allowing a passive diffusion of ions and small molecules between adjacent cells. Connexin43, the main channel-forming protein expressed in ventricular myocytes, can associate with zonula occludens-1, a scaffolding protein linked to the actin cytoskeleton and to signal transduction molecules. The possible influence of Rho GTPases, major regulators of cellular junctions and of the actin cytoskeleton, in the modulation of gap junctional intercellular communication (GJIC) was examined. The activation of RhoA by cytoxic necrotizing factor 1 markedly enhanced GJIC, whereas its specific inhibition by the Clostridium botulinum C3 exoenzyme significantly reduced it. RhoA activity affects GJIC without major cellular redistribution of junctional plaques or changes in the Cx43 phosphorylation pattern. As these GTPases frequently act via the cortical cytoskeleton, the importance of F-actin in the modulation of GJIC was investigated by means of agents interfering with actin polymerization. Cytoskeleton stabilization by phalloidin slowed down the kinetics of channel rundown in the absence of ATP, whereas its disruption by cytochalasin D rapidly and markedly reduced GJIC despite ATP presence. Cytoskeleton stabilization by phalloidin markedly reduced the consequences of RhoA activation or inactivation. This mechanism appears to be the first described capable to both up- or down-regulate GJIC through RhoA activation or, conversely, inhibition. The inhibition of Rho downstream kinase effectors had no effect on GJIC. The present results provide further insight into the gating and regulation of junctional channels and identify a new downstream target for the small G-protein RhoA.

Received for publication, February 26, 2008 , and in revised form, July 21, 2008.

^* This work was supported in part by grants from the European Community Research and Technological Development Action QLG1-CT-1999-00516. 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 To whom correspondence should be addressed: Inst. de Physiologie et Biologie Cellulaires, UMR CNRS 6187, 40 ave. du recteur Pineau, F-86022 Poitiers, France. Tel./Fax: 33-549-45-37-51; E-mail: Jean.Claude.Herve{at}univ-poitiers.fr.

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