ALPHA1 ADRENOCEPTOR SUBTYPES AND ROLE IN PATHOPHYSIOLOGY

ALPHA1 肾上腺素受体亚型及其在病理生理学中的作用

• 批准号: 2908627
• 负责人: DIANNE M PEREZ
• 金额: $ 23.2万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2908627
• 关键词: alpha adrenergic receptor; alpha antiadrenergic agent; benzodiazepines; biological signal transduction; blood pressure; cardiovascular function; chimeric proteins; genetic strain; genetically modified animals; heart contraction; laboratory mouse; pathologic process; protein structure function; receptor binding; receptor expression

Our major objective is to elucidate the molecular and biochemical mechanisms both in vitro and in vivo involved in binding and activation of alpha1-adrenergic receptors (ARs) and its subsequent action on the autonomic nervous system. Alpha1-adrenergic receptors are members of the G-protein-coupled receptor family of proteins that mediate the effects of the sympathetic nervous system by binding the endogenous neurotransmitters, epinephrine and norepinephrine. Signal transduction by alpha1-ARs is involved in a variety of responses such as neurotransmission, smooth muscle contraction, cardiac and other organ system homeostasis. These receptors are a therapeutic target in the current management of hypertension, benign prostatic hypertrophy and impotence. Alterations in the signaling pathways and/or receptors themselves may contribute to the pathogenesis of neurological and cardiovascular diseases. Thus, a detailed understanding of the structure-function of these receptors and their signal transduction mechanisms will be crucial to our understanding of the pathology and treatment of these diseases. Our laboratory has made considerable strides into the structure-function of alpha1-ARs subtypes (alpha1a, alpha1b, alpha1d) by characterizing determinants in the binding pocket that contribute to agonist binding and subtype selectivity. We have also through the use of constitutively active mutations provided insights into the activation mechanism. Based on these results, we now propose to address the following specific aims on structure-function analysis in vitro by concentrating on how antagonists and benzodiazepines bind and modulate alpha1-AR function and the mechanism of the poor efficacy of the alpha1d-subtype. This will enhance our understanding of the binding pocket, the signaling differences between alpha1-subtypes and may enhance new drug design. We will also explore possible pathologies from alpha1-subtype overactivity in vivo and to more clearly define the role of the alpha1a-subtype in cardiovascular function.

我们的主要目的是阐明体内和体外α1肾上腺素能受体(ARs)结合和激活的分子和生化机制，以及它对自主神经系统的作用。α1肾上腺素能受体是G蛋白偶联受体家族的成员，通过结合内源性神经递质肾上腺素和去甲肾上腺素来介导交感神经系统的作用。α1-Ars的信号转导涉及多种反应，如神经传递、平滑肌收缩、心脏和其他器官系统的动态平衡。这些受体是目前治疗高血压、良性前列腺肥大和阳萎的治疗靶点。信号通路和/或受体本身的改变可能导致神经和心血管疾病的发病。因此，对这些受体的结构和功能及其信号转导机制的详细了解对于我们理解这些疾病的发病机制和治疗将是至关重要的。我们实验室通过表征结合口袋中有助于激动剂结合和亚型选择性的决定因素，在α1-Ars亚型(α1a、α1b、α1d)的结构功能方面取得了相当大的进展。我们还通过使用结构性活性突变提供了对激活机制的见解。基于这些结果，我们现在建议通过集中于拮抗剂和苯二氮卓类药物如何结合和调节α1-AR功能以及α1d亚型疗效差的机制来解决以下体外结构-功能分析的具体目标。这将增强我们对结合口袋、α1亚型之间的信号差异的理解，并可能促进新药设计。我们还将探索体内alpha1亚型过度活动的可能病理机制，并更清楚地确定alpha1a亚型在心血管功能中的作用。