MOLECULAR BASIS OF ALPHA ADRENERGIC RECEPTOR FUNCTION

儿茶酚胺，如神经递质去甲肾上腺素和激素 肾上腺素在神经和体液控制中起着至关重要的作用 整个循环。这些药物对人类健康的不同影响 心血管控制中心在大脑、血管系统、心脏和 血小板由多种受体亚型介导，这些受体亚型分为 萎缩α1、α2或β肾上腺素能受体。而且，这些药物 作用于这些受体的激动剂和拮抗剂是最多的 广泛用于治疗心血管疾病的药物，如 高血压和充血性心力衰竭。这笔赠款是为了 支持一项旨在阐明分子的基础研究计划 α-肾上腺素能激活和脱敏的基础 感受器。尽管我们研究的动力和长远目标是 阐明肾上腺素能的基本生化过程 循环的控制，这里提出的研究将利用作为 模型系统克隆并表达了这些受体的基因。这个 研究提案有几个相互关联的目标。这些都将增加 激动剂与受体结合方式的理解 通过中间的奎宁核苷酸调节蛋白传递信号 到生理效应物，如酶(磷脂酶C)或离子 并阐明这种信号传递的机制。 通过反调节脱敏机制迅速减弱。这些 目标将通过以下方式实现：1)克隆、表达和鉴定 一种药理学上定义的α-肾上腺素能受体，它具有 远未克隆(α1a)。将比较其信令特性 与其他三个克隆的α1-肾上腺素能受体的同源性。2) 开发新的方法来阻断通过 α-肾上腺素能受体，可作为后续研究的基础 新型α-肾上腺素能拮抗剂的设计。3)阐明本质 和磷酸化反应的后果，这些反应调节着 不同的α-肾上腺素能受体亚型的派别。通过生产 关于阿尔法-阿尔法的基本过程的新信息 肾上腺素能受体被激活和脱敏这项研究应该 为药物和新药的设计提供分子基础 增强我们操纵心血管α-受体的能力的策略 肾上腺素能受体信号转导机制在人类治疗中的作用 充血性心力衰竭和高血压等疾病。

Catecholamines such as the neurotransmitter norepinephrine and the hormone epinephrine are of vital importance in the neural and humoral control of the entire circulation. The diverse effects of these agents on cardiovascular control centers in the brain, on the vasculature, heart and platelets are mediated by a multiplicity of receptor subtypes classified as wither alpha1, alpha2 or beta-adrenergic receptors. Moreover, drugs which act on these receptors as agonists and antagonists are amongst the most widely used agents in the treatment of cardiovascular disorders such as hypertension and congestive heart failure. This grant is requested to support a program in basic research directed at elucidating the molecular basis for the activation and desensitization of the alpha-adrenergic receptors. Although the impetus to and long range goal of our studies is to shed light on the basic biochemical process underlying adrenergic control of the circulation, the research proposed here will utilize as model systems the cloned and expressed genes for these receptors. The research proposal has several interrelated goals. These are to increase understanding of the ways in which agonist binding ot the receptors transmits signals via intermediary quanine nucleotide regulatory proteins to physiological effectors such as enzymes (phospholipase C) or ion channels and to elucidate the mechanisms by which such signalling is rapidly attenuated by counter-regulatory desensitization mechanisms. These goals will be accomplished by: 1) cloning, expressing and characterizing the one pharmacologically defined alpha1-adrenergic receptor which has thus far not been cloned (alpha1A). Its signalling properties will be compared with those of the three other cloned alpha1-adrenergic receptors. 2) Developing novel approaches to interdicting the signalling mediated via alpha-adrenergic receptors which may serve as the basis for subsequent design of novel alpha-adrenergic antagonists. 3) Elucidating the nature and consequences of the phosphorylation reactions which regulate the factions of the different alpha-adrenergic receptor subtypes. By producing new information bout the fundamental processes by which the alpha- adrenergic receptors ar activated and desensitized this research should provide the molecular underpinning for the design of drugs and novel strategies to enhance our ability to manipulate cardiovascular alpha- adrenergic receptor signalling mechanisms for therapeutic benefit in human illnesses such as congestive heart failure and hypertension.