AGE AND VASCULAR ALPHA-ADRENOCEPTOR FUNCTIONAL COUPLING

肾上腺素能受体的信号转导受一种独特的 鸟嘌呤核苷酸结合蛋白（G蛋白）阵列。 我们 初步数据表明，在主动脉中，α 1b-肾上腺素受体（AR） 与Go和Gq都有联系，而（alpha 1d）AR只与Go和Gq相关联。 Gq。 此外，在不同的组织中，不同的a1 AR亚型的水平也不同。 血管是不同的。 这些结果表明，差异 α 1 AR亚型与G蛋白的偶联可能发生在不同的血液中， 船舶. 这些数据进一步表明，年龄相关的改变， 特异性受体及其相关G蛋白相互作用可 显着影响受体介导的信号传导，并最终 器官的功能。 血液中α-和β-AR功能的变化 在Fisher-344大鼠和人中均报道了血管。 在 此外，（α）1AR表达的年龄相关性改变 在大鼠主动脉中也观察到亚型。 随着衰老 在介导心血管疾病发病机制中的重要作用 疾病，如高血压、直立性低血压和 动脉粥样硬化的分子机制的研究是非常重要的 在衰老过程中导致血管功能改变。 拟议 一项研究旨在验证一种假设，即阿尔法的不同成分 (1)AR/G蛋白调节不同的跨膜信号传导阵列 血管系统中的通路，其受年龄的不同影响。 我们 提出了一系列的实验来充分描述 改变的（α 1）ARv亚型/G蛋白与年龄相关的 血管系统中（α 1）AR介导功能的变化。 具体而言，我们将直接评估（α 1）肾上腺素受体的联系 年轻和老年大鼠的腹主动脉和尾动脉中的G蛋白。 将使用为血管制备的膜来确定 α 1肾上腺素受体亚型与G蛋白的偶联 使用特异性抗G（α） 或抗α 1 AR抗体。 此外，我们将定义 α 1 AR变化的分子机制 转导系统在老化和测试的特异性， 关于（α 1 AR、G蛋白和 血管 本提案的结果将大大提高 我们对信号转导通路在细胞凋亡中的作用的认识， 年龄相关性心血管疾病的病理生理学， 帮助设计更有效的药物治疗的具体策略 老年患者的这些疾病。

Signal transduction for adrenergic receptors is regulated by a distinct array of guanine nucleotide binding proteins (G proteins). Our preliminary data indicate that in aorta, (alpha 1b-adrenoceptors (ARs) are linked to both Go and Gq, while (alpha 1d)ARs couple exclusively to Gq. In addition, the levels of various a1 AR subtypes in different blood vessels were different. These results suggest that differential coupling of a1 AR subtypes to G proteins may occur in different blood vessels. These data furthermore suggest that age-related altering the interaction of specific receptor and its associated G protein(s) may significantly affect the receptor-mediated signaling and ultimately the function of the organ. Changes in alpha-and B-AR functions in blood vessels have been reported both in Fisher-344 rats and human. IN addition, an age-related alterations in expression of (alpha)1AR subtypes has also been observed in rat aorta. As aging plays an significant role in mediating the pathogenesis of cardiovascular disease, such as hypertension, orthostatic hypotension and atherosclerosis, it is important to study the molecular mechanism (s) contributing to altered vascular function during aging. The proposed study aims to test the hypothesis that different compositions of alpha (1)AR/G proteins regulate diverse arrays of transmembrane signalling pathways n vasculature which are differentially affected by age. We are proposing a series of experiments to fully characterize the contribution of altered (alpha 1)ARv subtypes/G proteins coupling to the age-related changes in (alpha 1) AR- mediated functions i vasculature. Specifically, we will directly assess linkage of (alpha1) adrenoceptors with G proteins in aortas and tail arteries from young and old rats. Membranes prepared for blood vessels will be used to determine the coupling of (alpha1)-adrenoceptor subtypes to G proteins by an established immunoprecipitation procedure using specific anti-G(alpha) or anti (alpha1 AR antibodies. In addition, we will define the molecular mechanisms responsible for the changes in alpha1 AR transduction systems during aging and test the specificity of these alterations with respect to subclasses of (alpha1 AR, G proteins and blood vessels. Results from the present proposal will greatly enhance our knowledge of the role of the signal transduction pathways in the pathophysiology of age-related cardiovascular diseases and ultimately help in designing specific strategies for more effective pharmacotherapy of those disorders in geriatric patients.