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J. Biol. Chem., Vol. 282, Issue 8, 5488-5495, February 23, 2007

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Epac-mediated Activation of Phospholipase C Plays a Critical Role in -Adrenergic Receptor-dependent Enhancement of Ca²⁺ Mobilization in Cardiac Myocytes^*

Emily A. Oestreich, Huan Wang, Sundeep Malik, Katherine A. Kaproth-Joslin^¶, Burns C. Blaxall^||, Grant G. Kelley^¶**, Robert T. Dirksen, and Alan V. Smrcka¹

From the Departments of Pharmacology and Physiology and the ^||Cardiovascular Research Institute, University of Rochester School of Medicine, Rochester, New York 14642, Systems Biology Division, The Wistar Institute, Philadelphia, Pennsylvania, 19104, and Departments of ^¶Pharmacology and ^**Medicine, SUNY Upstate Medical University, Syracuse, New York 13210

Recently we demonstrated that PLC plays an important role in -adrenergic receptor (AR) stimulation of Ca²⁺-induced Ca²⁺ release (CICR) in cardiac myocytes. Here we have reported for the first time that a pathway downstream of AR involving the cAMP-dependent Rap GTP exchange factor, Epac, and PLC regulates CICR in cardiac myocytes. To demonstrate a role for Epac in the stimulation of CICR, cardiac myocytes were treated with an Epac-selective cAMP analog, 8-4-(chlorophenylthio)-2'-O-methyladenosine-3',5'-monophosphate (cpTOME). cpTOME treatment increased the amplitude of electrically evoked Ca²⁺ transients, implicating Epac for the first time in cardiac CICR. This response is abolished in PLC^-/- cardiac myocytes but rescued by transduction with PLC, indicating that Epac is upstream of PLC. Furthermore, transduction of PLC^+/+ cardiac myocytes with a Rap inhibitor, RapGAP1, significantly inhibited isoproterenol-dependent CICR. Using a combination of cpTOME and PKA-selective activators and inhibitors, we have shown that AR-dependent increases in CICR consist of two independent components mediated by PKA and the novel Epac/PLC pathway. We also show that Epac/PLC-dependent effects on CICR are independent of sarcoplasmic reticulum loading and Ca²⁺ clearance mechanisms. These data define a novel endogenous PKA-independent AR-signaling pathway through cAMP-dependent Epac activation, Rap, and PLC that enhances intracellular Ca²⁺ release in cardiac myocytes.

Received for publication, September 5, 2006 , and in revised form, December 8, 2006.

^* This work was supported by National Institutes of Health Grants GM053536 (to A. V. S.), DK56294 (to G. G. K.), and AR44657 (to R. T. D.), an American Heart Association Scientist Development grant (to B. C. B.), and Oral Cellular and Molecular Biology Training Grant T32 DE07202-15 (to E. A. O.). 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: Dept. of Pharmacology and Physiology, University of Rochester School of Medicine, 601 Elmwood Ave., Box 711, Rochester, NY 14642. Tel.: 585-275-0892; Fax: 585-273-2652; E-mail: alan_smrcka{at}urmc.rochester.edu.

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