NEUROCHEMICAL ACTIONS OF PSYCHOTROPIC DRUGS

精神药物的神经化学作用

• 批准号: 6128810
• 负责人: SOLOMON H. SNYDER
• 金额: $ 107.53万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6128810
• 关键词: NMDA receptors; brain metabolism; genetically modified animals; glutamate receptor; immunocytochemistry; in situ hybridization; inositol phosphates; laboratory mouse; laboratory rat; neurochemistry; nitric oxide synthase; pharmacokinetics; protein localization; protein metabolism; protein protein interaction; protein purification; psychopharmacology; psychotropic drugs; receptor binding; second messengers; serine; synapsins; tissue /cell culture; yeast two hybrid system

DESCRIPTION(Adapted from applicant's abstract): The long term goal of this application over the past 30 years has been to elueidate molecular signaling systems in the brain whieh may be relevant to aetions of psyehotropic drugs. We propose continuing a characterization of multiple systems but with a special foeus on three: D-serine, neuronal nitric oxide synthase (nNOS) associated proteins, and higher inositol polyphosphates. (1) D-serine: We will extend our evidence for D-serine as a neuromodulator serving as the endogenous ligand for NMDA-glutamate receptors. We will eharaeterize serine racemase, the enzyme we have recently purified and cloned, which converts L- to D-serine. We will develop knockouts and transgenics for serine racemase and d-amino aeid oxidase, the enzyme which appears to physiologically degrade D-serine. (2) nNOS Associated Proteins-Focus on CAPON: CAPON is a nNOS associated protein we discovered, which may serve as a scaffold linking nNOS to other proteins. We recently discovered interactions of CAPON with synapsin, a synaptie vesicle protein, and Dexrasl, a new member of the Ras family. We will continue our studies implicating CAPON as a bridge delivering NO formed by nNOS to synapsin to affect synaptic vesiele funetion, and to Dexrasl to influenee its downstream signaling to alter nuelear funetion. (3) Higher Inositol Polyphosphates: Higher inositol polyphosphates are pyrophosphates with e about :-rgetic phosphate groups that we think may mediate phosphate transfer to proteins, perhaps assoeiated with synaptic vesicle turnover. We will extend our studies in which we purified and cloned IP 6 kinase, which forms the pyrophosphate PP-IPs (IP7 ). We will characterize functions of this enzyme and a related protein, PiUS that also possesses IP6 kinase activity. We will characterize putative protein phosphorylation by PP-IP 5. We will also complete purif aboutcation and cloning of PP-IPs kinase which forms bis PP-IP4, which contains two pyrophosphate groups

描述（改编自申请人的摘要）： 过去 30 年来该应用程序的长期目标是 阐明大脑中可能与相关的分子信号系统 精神药物的作用。我们建议继续描述 多个系统，但特别关注三个系统：D-丝氨酸、神经元硝酸 氧化物合酶 (nNOS) 相关蛋白和高级肌醇多磷酸盐。 (1) D-丝氨酸：我们将扩展 D-丝氨酸作为神经调节剂的证据 作为 NMDA-谷氨酸受体的内源性配体。我们将 eharaeterize 丝氨酸消旋酶，我们最近纯化和克隆的酶， 它将 L-丝氨酸转化为 D-丝氨酸。我们将开发基因敲除和转基因技术 丝氨酸消旋酶和 d-氨基酸氧化酶，该酶似乎 生理上降解 D-丝氨酸。 (2) nNOS相关蛋白——聚焦CAPON： CAPON是我们发现的一种nNOS相关蛋白，可作为支架 将 nNOS 与其他蛋白质连接起来。我们最近发现了 CAPON 的相互作用 含有突触蛋白（一种突触小泡蛋白）和 Dexrasl（Ras 的新成员） 家庭。我们将继续研究 CAPON 作为交付的桥梁 nNOS 与突触蛋白形成的 NO 影响突触小泡功能，并 Dexrasl 影响其下游信号传导以改变核功能。 (3) 高级肌醇多磷酸盐：高级肌醇多磷酸盐是 带有 e 的焦磷酸盐：我们认为可能介导的活性磷酸基团 磷酸盐转移到蛋白质，可能与突触小泡有关 周转。我们将扩展我们的研究，其中我们纯化并克隆了 IP 6 激酶，形成焦磷酸 PP-IP (IP7)。我们将表征 该酶和同样具有 IP6 的相关蛋白 PiUS 的功能 激酶活性。我们将通过 PP-IP 表征假定的蛋白质磷酸化 5. 我们还将完成PP-IPs激酶的纯化和克隆。 形成双 PP-IP4，其中含有两个焦磷酸基团