ALPHA1-ADRENERGIC SIGNALING PATHWAYS IN HEART

α/1-肾上腺素能受体（AR）的激活是一个重要的引发剂， 心脏肥大反应的最后阶段 遗传和形态变化的特征。两种类型的 α/1-AR在心肌细胞中表达，α/1A-AR和α/1B-AR 亚型α/1A-和α/1B-AR亚型都与G蛋白偶联 由产生分叉信号的α-伽马亚单位组成 通过α-和β-γ-介导的下游效应物的调节。 我们最近的数据表明，通过α和β-γ介导的 调节下游效应物。我们最近的数据表明， α/1A和α/1B-AR亚型的激活以及通过 需要G蛋白α和β γ介导的信号， 引出肥大反应的所有特征。为了验证这一 假设，将解决以下具体目标：1）确定 α/1A-和α/1B-AR亚型在激活 不同的信号通路，最终，不同的生物学 与心脏肥大相关的终点; 2）识别区域 α/1A-和α/1B-AR亚型，负责 信号通路的差异激活; 3）检查 各种G蛋白α和β γ在生殖中的作用 激活不同的信号通路，最终， 生物反应;和4）确定功能的相互作用， α/1A-和α/1B-AR亚型具有不同的G 蛋白质α-γ亚单位。方法是操纵 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亚型和丝裂原 活化的蛋白激酶（MAPK/JNK/P38）以调节的方式，使用 遗传学和反向遗传学方法的组合。然后，PLC和 MAPK/JNK/p38信号通路将被重新检查其依赖于 目标组件。形态和基因表达的变化， 代表信号通路的终点，也将被检查， 它们对目标组件的依赖性。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 抵消心脏中的α/1-AR亚型特异性作用。

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.