ALPHA1-ADRENERGIC SIGNALING PATHWAYS IN HEART

α/1-肾上腺素能受体(AR)的激活是一种重要的启动机制 心脏的过度营养反应，最终导致 遗传和形态变化的特征集合。两种类型的 α/1-AR在心肌细胞中表达，α/1A-AR和α/1B-AR 子类型。α/1A-和α/1B-AR亚型都与G蛋白偶联 由产生分叉信号的Alphabetagma亚基组成 通过阿尔法和贝塔格玛介导的下游效应器的调节。 我们最近的数据表明，通过阿尔法和贝塔格玛介导的 对下游效应器的监管。我们最近的数据表明 α/1A和α/1B-AR亚型的激活和通过 G蛋白α和β蛋白介导的信号都是必需的 引出肥大反应的所有特征。为了测试这一点 假设，将解决以下具体目标：1)确定 α/1A-和α/1B-AR亚型在血管紧张素转换酶激活中的作用 不同的信号通路，最终，不同的生物 与心肌肥厚相关的终点；2)识别区域 阿尔法/1A和阿尔法/1B-AR亚型中负责 信号通路的差异激活；3)检查 不同G蛋白α和β蛋白在生殖中的作用 激活不同的信号通路，最终，不同的 生物反应；以及4)确定功能相互作用 具有不同G组合的Alpha/1A和Alpha/1B-AR亚型 蛋白质甲胎蛋白亚基。方法将是操纵 α/1A-AR之间信号通路中的潜在成分 亚型和磷脂酶C(PLC)和α/1B-AR亚型和有丝分裂原 激活的蛋白激酶(MAPK/JNK/P38)以受调控的方式，使用一种 遗传学和反向遗传学方法的结合。然后，PLC和 MAPK/JNK/p38信号通路的依赖性将被重新检测 目标组件。形态和基因表达的变化，这 代表信号通路的端点，也将被检查 它们对目标组件的依赖。这些研究是至关重要的 用于设计新的治疗策略，旨在增强或 对抗心脏中的α/1-AR亚型特异性效应。

Activation of alpha/1-adrenergic receptors (AR) is an important initiator of the cardiac hyper-trophic response, which culminates in a characteristic set of genetic and morphologic changes. Two types of alpha/1-AR are expressed in cardiac myocytes, the alpha/1A-and alpha/1B-AR subtypes. Both the alpha/1A- and alpha/1B-AR subtypes couple to G proteins composed of alphabetagamma subunits, which produce bifurcating signals through alpha- and betagamma-mediated regulation of downstream effectors. Our recent data suggest that through alpha- and betagamma-mediated regulation of downstream effectors. Our recent data suggest that activation of both alpha/1A and alpha/1B-AR subtypes and coupling through both G protein alpha- and betagamma-mediated signals are required to elicit all features of the hypertrophic response. To test this hypothesis, the following specific aims will be addressed: 1) To determine the roles of the alpha/1A- and alpha/1B-AR subtypes in activation of different signaling pathways, and ultimately, different biological endpoints associated with cardiac hypertrophy; 2) To identify the regions of the alpha/1A- and alpha/1B-AR subtypes that are responsible for differential activation of signaling pathways; 3) To examine the contributions of the various G protein alpha and betagamma in reproducing activation of different signaling pathways, and ultimately, different biological responses; and 4) To determine the functional interactions of the alpha/1A- and alpha/1B-AR subtypes with distinct combinations of G protein alphabetagamma subunits. The approach will be to manipulate potential components in the signaling pathways between the alpha/1A-AR subtype and phospholipase C (PLC) and the alpha/1B-AR subtype and mitogen activated protein kinases (MAPK/JNK/P38) in a regulated fashion, using a combination of genetics and reverse genetics approaches. Then, the PLC and MAPK/JNK/p38 signaling pathways will be reexamined for their dependence on the targeted components. Morphologic and gene expression changes, which represent the endpoints of signaling pathways, will also be examined for their dependence on the targeted components. These studies are critical for the design of new therapeutic strategies aimed at enhancing or counteracting alpha/1-AR subtype specific effects in the heart.