Cardiac Opioid Receptor Activation and Protein Kinase C

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DESCRIPTION (provided by applicant): Opioid receptors belong to the family of G-protein coupled receptors (GPCRs) with seven transmembrane regions spanning the sarcolemmal membrane and are coupled to inhibitory G-proteins which activate hospholipase C (PKC) and protein kinase C (PKC). One or multiple PKC isoforms translocate from the cytosol to target membranes where phosphorylation of serine/threonine residues cause a cascade of myocyte protective events. To date, the effects of cardiac opiate receptor subtype activation and their intracellular signaling mechanisms in normal and ischemic myocardium have been conflicting. This training proposal will determine opioid receptor subtype modulation of cardiac myocyte excitation-contraction coupling via specific PKC isoforms. Specific aims will: 1) determine delta- and kappa-opioid receptor modulation of cardiac excitation-contraction coupling in intact myocardium and 2) determine opioid receptor mediated PKC isoform signaling and modulation of intracellular calcium.