MOLECULAR REGULATION OF CARDIAC ADRENERGIC RECEPTORS

去甲肾上腺素和肾上腺素等儿茶酚胺类物质 在整个血液循环的荷尔蒙控制中的重要性。 这些 化合物通过偶联的α-和β-肾上腺素能受体起作用 通过G蛋白转化为腺苷酸环化酶和磷脂酶 C以及离子通道。 在许多调节机制中， 受体功能，其中最重要的是磷酸化的 G蛋白偶联受体激酶（GRKs）新家族的受体 例如β-肾上腺素能受体激酶（betaARK）。 这笔赠款是 要求支持一项旨在阐明 在分子和生理水平上， 肾上腺素能和其他G蛋白偶联受体 激酶以及最近鉴定的独特的磷酸酶。 这些 酶分别介导快速激动剂促进的脱敏， 受体信号再敏感化。 此外， 心脏β-ARK最近被认为是 心力衰竭的病理生理学 因此，本研究 该提案有三个密切相关的目标，所有这些目标都涉及一个主要的 专注于G蛋白对肾上腺素能受体功能的调节- 偶联受体激酶作为获得增加的方法， 了解循环系统的正常和异常激素控制 功能 这些目标是：1）确定GRK作用的特异性 肾上腺素能和其他G蛋白偶联受体。 2)来定义 通过“敲除”GRK的基因或 在转基因动物中过表达GRKs或特异性抑制剂。 这些实验将使我们能够评估改变 通过操纵β ARK系统在体内研究心脏功能。 3)到 确定磷酸酶的性质、特性和调节， 逆转GRK的作用。 这些研究将全面了解 G蛋白偶联受体，其中详细的信息， 和细胞机制提供了理解 在完整动物中的生理后果。 此外，结果 有潜力为新的治疗策略指明方向 治疗心血管疾病

Catecholamines such as norepinephrine and epinephrine are of vital importance in the hormonal control of the entire circulation. These compounds act via alpha- and beta-adrenergic receptors which are coupled through G proteins to enzymes such as adenylyl cyclase and phospholipase C as well as ion channels. Amongst a number of mechanisms which regulate receptor function, one of the most important is phosphorylation of the receptors by a novel family of G protein-coupled receptor kinases (GRKs) such as the beta-adrenergic receptor kinase (betaARK). This grant is requested to support a program in basic research directed at elucidating at a molecular and physiological level the mechanisms of regulation of adrenergic and other G protein-coupled receptors by these receptor kinases as well as by a recently identified unique phosphatase. These enzymes mediate, respectively, rapid agonist-promoted desensitization and resensitization of receptor signaling. Moreover, abnormal function of cardiac betaARK has recently been implicated as potentially contributing to the pathophysiology of heart failure. Accordingly, this research proposal has three closely linked goals, all of which involve a primary focus on the regulation of adrenergic receptor function by the G protein- coupled receptor kinases as an approach to gaining increased understanding of the normal and abnormal hormonal control of circulatory function. These goals are: 1) To determine the specificity of GRK action on adrenergic and other G protein-coupled receptors. 2) To define the physiological role of GRK's in vivo by "knocking out" their genes or by overexpressing the GRKs or specific inhibitors in transgenic animals. These experiments will allow us to assess the feasibility of altering cardiac function in vivo by manipulation of the betaARK system. 3) To determine the nature, properties and regulation of the phosphatases which reverse the action of GRKs. These studies will produce a comprehensive picture of the regulation of G protein-coupled receptors in which detailed information about molecular and cellular mechanisms provides the basis for understanding physiological consequences in the intact animal. Moreover, the results have the potential to point the way toward novel therapeutic strategies for cardiovascular diseases.