Epac-mediated Activation of Phospholipase Cɛ Plays a Critical Role in β-Adrenergic Receptor-dependent Enhancement of Ca2+ Mobilization in Cardiac Myocytes
| Autor: | Alan V. Smrcka, Katherine A. Kaproth-Joslin, Huan Wang, Robert T. Dirksen, Emily A. Oestreich, Burns C. Blaxall, Sundeep Malik, Grant G. Kelley |
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| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_specialty
Adrenergic receptor GTP' Stimulation Biology Biochemistry Mice Phosphoinositide Phospholipase C Transduction Genetic Internal medicine Receptors Adrenergic beta Phosphoinositide phospholipase C Cyclic AMP medicine Animals Guanine Nucleotide Exchange Factors Myocyte Myocytes Cardiac Calcium Signaling Receptor Evoked Potentials Molecular Biology Cells Cultured Mice Knockout Phospholipase C Endoplasmic reticulum Cell Biology Cell biology Sarcoplasmic Reticulum rap GTP-Binding Proteins Endocrinology Type C Phospholipases cardiovascular system Calcium |
| Zdroj: | Journal of Biological Chemistry. 282:5488-5495 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m608495200 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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