5-HT RECEPTORS AND THEIR EFFECTORS

受体亚型的分类对于选择性治疗至关重要，对于 了解药物的作用模式并定义组织生理学。 了解受体功能的调节，即信号转导 特定细胞上多个受体之间的机制、功能相互作用 脱敏作用允许对药物进行与治疗相关的操作 活体内行动。这项提案的长期目标是划定 三种5-羟色胺触发的信号转导机制 哺乳动物组织中的受体亚型：5-HT1a和5-HT2受体 以及可能的受体亚型5-HT4，并研究 这些受体上的激动剂作用的调节，两种受体的调节 以及效应器系统的调制。为了实现这些目标1)5) HT4受体将被归类为三种哺乳动物制剂，其 效应者(S)将被确定；2)两个内生过程 参与5-HT2受体功能的调节(功能拮抗 和脱敏)将被表征；以及3) 5-HT1a受体的信号转导将被阐明。5-HT4 与大脑中的腺苷环化酶活性负相关的受体， 按5-羟色胺激动剂和拮抗剂进行分类。体外实验 百日咳毒素与受体刺激结合的GTP-γ-S会 测试G蛋白是否与4-HT4受体相连。共存 在人类大隐静脉的5-HT4和5-HT2受体中， 调节平滑肌收缩，提供了一个独特的机会 测试这些不同的受体是否共享相同的细胞内后 通过分析它们对钙通道配体的敏感性来阐明受体的作用机制。 5-HT2受体的脱敏和调节机制 将通过新的动力学方法来追求功能拮抗，从而使 我们来量化多状态转换的动力学。结构性 识别(结合)和激活5-HT1A所需的元素 将通过测试新型抗焦虑药物的类似物来评估受体 毒品丁螺环酮。三种功能5-羟色胺受体的协同研究 在哺乳动物组织中的研究有望提供对 哺乳动物组织中5-羟色胺受体的药理学和生理学 希望对5-羟色胺的药理学和生理学有深入的了解 受体及其在健康和疾病状态下与人类的关系。

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.