AGE AND VASCULAR ALPHA-ADRENOCEPTOR FUNCTIONAL COUPLING

肾上腺素能受体的信号转导受不同的 鸟嘌呤核苷酸结合蛋白(G蛋白)的阵列。我们的 初步数据表明，在主动脉中，(α1b-肾上腺素能受体(ARs) 都与围棋和GQ相关联，而(阿尔法1D)ARs仅与 GQ。此外，不同A1 AR亚型的水平也不同 血管不同。这些结果表明，差异 A1 AR亚型与G蛋白的偶联可能发生在不同的血液中 船只。这些数据进一步表明，与年龄相关的改变 特异性受体及其相关G蛋白(S)的相互作用可能 显著影响受体介导的信号转导，最终影响 器官的功能。血液中α-和B-AR功能的变化 在Fisher-344大鼠和人身上都有血管的报道。在……里面 此外，(α)1AR表达的年龄相关性变化 在大鼠的主动脉中也观察到了亚型。随着年龄的增长， 在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，研究其分子机制很重要(S) 在衰老过程中导致血管功能改变。建议数 这项研究旨在检验阿尔法成分不同的假设 (1)AR/G蛋白调节多种跨膜信号通路 受年龄影响不同的血管系统的通路。我们是 提出了一系列实验来充分表征这一贡献 与年龄相关的(α1)ARV亚型/G蛋白的改变 (α1)AR介导的功能变化I血管系统。 具体地说，我们将直接评估(Alpha1)肾上腺素受体的联系 在幼年和老年大鼠的主动脉和尾动脉中发现了G蛋白。 为血管准备的膜将用于确定 (α1)-肾上腺素受体亚型与G蛋白的偶联 建立了使用特异性抗G(α)的免疫沉淀程序 或抗(α1 AR抗体)。此外，我们还将定义 α1受体变化的分子机制 衰老过程中的转导系统，并测试这些信号转导系统的特异性 与(Alpha1 AR、G蛋白和 血管。目前提案的结果将大大提高 我们对信号转导通路在体内的作用的认识 年龄相关性心血管疾病的病理生理学和最终 帮助设计更有效的药物治疗的具体策略 在老年患者中的这些障碍。

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.