Cardiac Opioid Receptor Activation and Protein Kinase C

说明(申请人提供)：阿片受体属于G蛋白偶联受体(GPCRs)家族，具有跨越肌膜的七个跨膜区，并与激活磷脂酶C(PKC)和蛋白激酶C(PKC)的抑制性G蛋白偶联。一个或多个PKC亚型从胞浆转移到靶膜，在那里丝氨酸/苏氨酸残基的磷酸化导致一系列心肌细胞保护事件。到目前为止，心脏阿片受体亚型激活的作用及其细胞内信号机制在正常和缺血心肌中的作用一直相互矛盾。该训练方案将通过特定的PKC亚型确定阿片受体亚型对心肌细胞兴奋-收缩偶联的调节作用。具体目标包括：1)确定β阿片受体和kappa阿片受体对完整心肌兴奋收缩偶联的调节作用；2)确定阿片受体介导的PKC亚型信号传导和细胞内钙调节。

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.