5-HT RECEPTORS AND THEIR EFFECTORS

受体亚型的分类对于选择性治疗至关重要，因为 了解药物作用模式和定义组织生理学。 了解受体功能的调节，即信号转导 机制，给定细胞上多种受体之间的功能相互作用 并且脱敏允许对药物进行治疗相关的操作 体内作用。 本提案的长期目标是， 三种5-HT引发的信号转导的潜在机制 哺乳动物组织中的受体亚型：5-HT 1A和5-HT 2受体 沿着一种假定的受体亚型，5-HT 4，并研究 调节这些受体的激动剂作用，受体调节 以及调节效应器系统。 为了实现这些目标，1）5- HT 4受体将在三种哺乳动物制剂中分类，其 将鉴定效应物; 2）两种内源性过程， 参与5-HT 2受体功能的调节（功能性拮抗 和脱敏）将被表征;和3）初始步骤， 将阐明5-HT 1A受体的信号转导。 5-HT4 与脑中腺苷酸环化酶活性负相关的受体， 按5-HT激动剂和拮抗剂分为B类。 离体实验 与百日咳毒素和GTP-γ-S的受体刺激结合将 测试G蛋白是否与4-HT 4受体相连。 共存 5-HT 4和5-HT 2受体在人隐静脉，都是 介导平滑肌收缩，提供了独特的机会， 测试这些不同的受体是否共享相同的细胞内后- 通过测定它们对Ca++通道配体的敏感性来研究它们的受体机制。 5-HT_2受体的脱敏调节机制和5-HT_2受体的免疫调节机制 功能性拮抗作用将通过新的动力学方法进行， 我们来量化多状态转换的动态。 结构 识别（结合）和激活5-HT 1A所需的元件 受体将通过测试新的抗焦虑药的类似物来评估 药物丁螺环酮 这些协同研究的三个功能5-HT受体 在哺乳动物组织中的作用， 哺乳动物组织中5-HT受体的药理学和生理学研究， 预期提供深入了解5-HT的药理学和生理学 受体及其与人类健康和疾病状态的关系。

Classification of receptor subtypes is crucial for selective therapy, for understanding the mode of drug action and for defining tissue physiology. Understanding modulation of receptor function, i.e. the signal transduction mechanism, functional interaction among multiple receptors on a given cell and desensitization permits therapeutically relevant manipulation of drug action in vivo. The long term goals of this proposal are to delineate the underlying mechanisms of signal transduction triggered by three 5-HT receptor subtypes in mammalian tissues: the 5-HT1A and 5-HT2 receptors along with a putative receptor subtype, the 5-HT4 and to study the modulation of agonist action at these receptors, both receptor modulation as well as modulation of effector systems. Toward these goals 1) the 5- HT4 receptor will be classified in three mammalian preparations and its effector(s) will be identified; 2) two endogenous processes that participate in regulation of 5-HT2 receptor function (functional antagonism and desensitization) will be characterized; and 3) the initial steps in signal transduction of the 5-HT1A receptor will be elucidated. The 5-HT4 receptor which is negatively linked to adenylate cyclase activity in brain, will b classified by 5-HT agonists and antagonists. Ex vivo experiments with pertussis toxin and receptor-stimulated binding of GTP-gamma-S will test whether G-proteins are linked to the 4-HT4 receptor. The coexistence of the 5-HT4 and the 5-HT2 receptors in the human saphenous vein, both of which mediate smooth muscle contraction, provides a unique opportunity to test whether these distinct receptors share the same intracellular post- receptor mechanism by assaying their sensitivity to Ca++ channel ligands. The mechanisms of 5-HT2 receptor regulation by desensitization and by functional antagonism will be pursued by novel kinetic methods which enable us to quantitate the dynamics of multiple state conversion. Structural elements require for recognition (binding) and for activation of the 5-HT1A receptors will be evaluated by testing analogs of the novel anxiolytic drug, buspirone. These concerted studies of three function 5-HT receptors in mammalian tissues are expected to provide an insight into the pharmacology and physiology of 5-HT receptors in mammalian tissues are expected to provide an insight int the pharmacology and physiology of 5-HT receptors and their relationship to human in health and disease states.