MECHANISMS OF MUSCARINIC RECEPTOR CROSS-TALK IN BRAIN

这项提议的目的是促进候选人作为一名 膜受体领域的独立研究员和 大脑内的细胞内信号。候选人的近期目标 是开发一个研究计划，调查通过什么机制 M受体信号转导机制与其他受体相互作用 大脑不同区域的系统以及精神药物是如何干预的 或调节这些相互作用。候选人的长期目标是 建立受体间相互作用的功能意义 大脑中的信号机制，这些机制如何影响神经元 兴奋性、学习、记忆力和行为。一家银行的财政支持 研究职业发展奖将使首席调查员能够 花更多的时间做研究和学习新技术来实现他的 远景目标。作为该大学药理学系的一名成员 加州大学欧文分校的候选人将有足够的机会 与该领域的其他知名调查人员合作 神经科学和心血管药理学。《公约》的具体目标 候选人的研究提案是为了调查 M受体激活对其他受体系统的影响 在完整的细胞制剂中刺激腺苷环化酶活性 腮腺和大脑的不同区域。DIRECT的贡献 M受体介导的腺苷环化酶抑制作用 抑制性鸟嘌呤核苷酸结合蛋白将使用 百日咳毒素可防止这种作用。丹参的药理亚型 M受体介导肌醇磷脂水解酶及其抑制作用 腺苷环化酶活性将在相同的制剂中定义 纹状体和腮腺的药理零点法和 放射性配基结合方法分析选择性的性质 M受体激动剂和拮抗剂。类似的方法将被用于 确定参与串扰的M受体的亚型 其他刺激腺苷环化酶活性的受体。最后， 各种具有精神药理作用的药物的作用机制 (抗精神病药、三环类抗抑郁药、锂)干扰 我们将研究M受体偶联的机制。结果是 这些研究可能揭示大脑中新的胆碱能机制 可能在阿尔茨海默病和其他精神障碍中受损 胆碱能功能减退。

The aims of this proposal are to enhance the candidate's development as an independent investigator in the field of membrane receptors and intracellular signalling within the brain. The candidate's immediate goals are to develop a research program investigating the mechanisms by which muscarinic receptor signalling mechanisms interact with other receptor systems in various regions of the brain and how psychiatric drugs interfere or modulate these interactions. The long range goals of the candidate are to establish the functional significance of interactions between receptor signalling mechanisms in the brain, how these mechanisms influence neuronal excitability, learning, memory and behavior. The financial support of a Research Career Development award will enable the principal investigator to spend more time doing research and learning new techniques to achieve his long range goals. As a member of the Department of Pharmacology at the University of California, Irvine, the candidate will have ample opportunity to collaborate with other established investigators within the field of neuroscience and cardiovascular pharmacology. The specific aims of the candidate's research proposal are to investigate the influence of muscarinic receptor activation on the ability of other receptor systems to stimulate adenylate cyclase activity in intact cell preparations of the parotid gland and various regions of the brain. The contribution of direct muscarinic receptor-mediated inhibition of adenylate cyclase activity via the inhibitory guanine nucleotide binding protein will be assessed using pertussis toxin to prevent this effect. The pharmacological subtypes of the muscarinic receptor mediating phosphoinositide hydrolysis and inhibition of adenylate cyclase activity will be defined in identical preparations of the corpus striatum and parotid gland using pharmacological null methods and radioligand binding methods to analyze the properties of selective muscarinic agonists and antagonists. Similar methods will be used to identify the subtype of the muscarinic receptor involved in cross-talk with other receptors that stimulate adenylate cyclase activity. Finally, the mechanisms by which various drugs of psychopharmacological interest (neuroleptics, tricyclic antidepressants, lithium) interfere with muscarinic receptor coupling mechanisms will be investigated. The results of these studies may reveal new cholinergic mechanisms in the brain which may be compromised in Alzheimer's disease and other mental disorders of cholinergic hypofunction.