MOLECULAR BASIS OF ALPHA ADRENERGIC RECEPTOR FUNCTION

神经递质去甲肾上腺素和激素 肾上腺素是至关重要的神经和体液控制 整个循环。 这些药物对 心血管控制中心在大脑中，在脉管系统，心脏和 血小板由多种受体亚型介导，这些受体亚型被分类为 使α 1、α 2或β-肾上腺素能受体萎缩。 此外， 作为激动剂和拮抗剂作用于这些受体， 广泛用于治疗心血管疾病的药物，例如 高血压和充血性心力衰竭。 申请该补助金的目的是 支持一项旨在阐明分子生物学的基础研究计划， α-肾上腺素能神经元激活和脱敏的基础 受体。 虽然我们学习的动力和长远目标是 来阐明肾上腺素能神经元 控制流通，这里提出的研究将利用作为 这些受体的克隆和表达基因的模型系统。 的 研究计划有几个相互关联的目标。 这些都是为了增加 了解激动剂与受体结合的方式 通过中间的鸟嘌呤核苷酸调节蛋白传递信号 生理效应物，如酶（磷脂酶C）或离子 通道，并阐明这种信号传导的机制， 通过反调节脱敏机制迅速减弱。 这些 目标将通过：1）克隆、表达和表征 一种已知的α 1-肾上腺素能受体， 尚未克隆（alpha 1A）。 它的信号特性将比较 与其他三种克隆的α 1肾上腺素能受体相同。 （二） 开发新的方法来阻断通过以下途径介导的信号传导 α-肾上腺素能受体，这可能是随后的基础 新型α-肾上腺素能拮抗剂的设计。 3)阐明自然 和磷酸化反应的后果， 不同的α-肾上腺素能受体亚型的亚型。 通过产生 关于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 为药物设计提供分子基础， 增强我们控制心血管α-受体的能力 用于人类治疗益处的肾上腺素能受体信号传导机制 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.