Epac-mediated Activation of Phospholipase C(Epsilon) Plays a Critical Role in Beta-adrenergic Receptor-dependent Enhancement of Ca2+ Mobilization in Cardiac Myocytes.
From: Department of Pharmacology, University of Rochester School of Medicine, Rochester, New York 14642, USA.
The Journal of biological chemistry
- Publish Date: Feb 2007
- ISSN: 0021-9258
- Volume: 282
- Issue: 8
- Pages: 5488-95
- Medium: Print
- Language: English
- Citation (JAMA): Oestreich Emily A, Wang Huan, Malik Sundeep, et al. Epac-mediated Activation of Phospholipase C(Epsilon) Plays a Critical Role in Beta-adrenergic Receptor-dependent Enhancement of Ca2+ Mobilization in Cardiac Myocytes.. J. Biol. Chem. Feb 2007;282:5488-95
Abstract
Recently we demonstrated that PLC(epsilon) plays an important role in beta-adrenergic receptor (betaAR) stimulation of Ca(2+)-induced Ca(2+) release (CICR) in cardiac myocytes. Here we have reported for the first time that a pathway downstream of betaAR involving the cAMP-dependent Rap GTP exchange factor, Epac, and PLC(epsilon) 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 Ca(2+) transients, implicating Epac for the first time in cardiac CICR. This response is abolished in PLC(epsilon)(-/-) cardiac myocytes but rescued by transduction with PLC(epsilon), indicating that Epac is upstream of PLC(epsilon). Furthermore, transduction of PLC(epsilon)(+/+) 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 betaAR-dependent increases in CICR consist of two independent components mediated by PKA and the novel Epac/(epsilon) pathway. We also show that Epac/PLC(epsilon)-dependent effects on CICR are independent of sarcoplasmic reticulum loading and Ca(2+) clearance mechanisms. These data define a novel endogenous PKA-independent betaAR-signaling pathway through cAMP-dependent Epac activation, Rap, and PLC(epsilon) that enhances intracellular Ca(2+) release in cardiac myocytes.
Mesh Headings (Keywords): Animals, Calcium, Calcium Signaling, Cells, Cultured, Cyclic AMP, Evoked Potentials, Guanine Nucleotide Exchange Factors, Mice, Mice, Knockout, Myocytes, Cardiac, Phosphoinositide Phospholipase C, Receptors, Adrenergic, beta, Sarcoplasmic Reticulum, Transduction, Genetic, Type C Phospholipases, rap GTP-Binding Proteins
Check for Full Text / PubMed Unique Identifier (PMID): 17178726
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