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J. Biol. Chem., Vol. 280, Issue 19, 18881-18890, May 13, 2005

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The Cytosolic Phospholipase A₂ Pathway, a Safeguard of ₂-Adrenergic Cardiac Effects in Rat^*

Bouziane Ait-Mamar, Michel Cailleret, Catherine Rucker-Martin¶, Anissa Bouabdallah, Gabriele Candiani, Christophe Adamy, Philippe Duvaldestin, Francoise Pecker, Nicole Defer, and Catherine Pavoine||

From the Inserm, U581, University of Paris, XII-Val de Marne, Créteil F-94010, France, the Service Anesthésie et Réanimation, Hôpital Henri Mondor, Créteil, F-94010, France, and ^¶CNRS, UMR-8078, Hôpital Marie-Lannelongue, Le Plessis-Robinson, F-92350, France

We have recently demonstrated that in human heart, ₂-adrenergic receptors (₂-ARs) are biochemically coupled not only to the classical adenylyl cyclase (AC) pathway but also to the cytosolic phospholipase A₂ (cPLA₂) pathway (Pavoine, C., Behforouz, N., Gauthier, C., Le Gouvello, S., Roudot-Thoraval, F., Martin, C. R., Pawlak, A., Feral, C., Defer, N., Houel, R., Magne, S., Amadou, A., Loisance, D., Duvaldestin, P., and Pecker, F. (2003) Mol. Pharmacol. 64, 1117–1125). In this study, using Fura-2-loaded cardiomyocytes isolated from adult rats, we showed that stimulation of ₂-ARs triggered an increase in the amplitude of electrically stimulated [Ca²⁺]_i transients and contractions. This effect was abolished with the PKA inhibitor, H89, but greatly enhanced upon addition of the selective cPLA₂ inhibitor, AACOCF₃. The ₂-AR/cPLA₂ inhibitory pathway involved G_i and MSK1. Potentiation of ₂-AR/AC/PKA-induced Ca²⁺ responses by AACOCF₃ did not rely on the enhancement of AC activity but was associated with eNOS phosphorylation (Ser¹¹⁷⁷) and L-NAME-sensitive NO production. This was correlated with PKA-dependent phosphorylation of PLB (Ser¹⁶). The constraint exerted by the ₂-AR/cPLA₂ pathway on the ₂-AR/AC/PKA-induced Ca²⁺responses required integrity of caveolar structures and was impaired by Filipin III treatment. Immunoblot analyses demonstrated zinterol-induced translocation of cPLA and its cosedimentation with MSK1, eNOS, PLB, and sarcoplasmic reticulum Ca²⁺ pump (SERCA) 2a in a low density caveolin-3-enriched membrane fraction. This inferred the gathering of ₂-AR signaling effectors around caveolae/sarcoplasmic reticulum (SR) functional platforms. Taken together, these data highlight cPLA as a cardiac ₂-AR signaling pathway that limits ₂-AR/AC/PKA-induced Ca²⁺ responses in adult rat cardiomyocytes through the impairment of eNOS activation and PLB phosphorylation.

Received for publication, September 8, 2004 , and in revised form, January 31, 2005.

^* This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale and The Fondation de France. 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: Unité INSERM 581, Hôpital Henri Mondor, 94010 Créteil, France. Tel.: 33-1-49-81-35-34; Fax: 33-1-48-98-09-08; E-mail: pavoine{at}im3.inserm.fr.

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