NEUROCHEMICAL ACTIONS OF PSYCHOTROPIC DRUGS

精神药物的神经化学作用

• 批准号: 6741429
• 负责人: SOLOMON H. SNYDER
• 金额: $ 113.83万
• 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/6741429
• 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)： 这个应用程序在过去30年的长期目标是 脑内洗脱的分子信号系统可能与 精神安慰剂的应用。我们建议继续描述 多个系统，但在三个系统上有一个特殊的敌人：D-丝氨酸，神经元一氧化氮 氧化物合成酶(NNOS)相关蛋白，以及较高的肌醇多聚磷酸。 (1)D-丝氨酸：我们将扩大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。我们会 我们最近提纯和克隆的丝氨酸外消旋酶， 将L-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，这种酶似乎 生理上降解D-丝氨酸。(2)nNOS相关蛋白-关注Capon： Capon是我们发现的一种nNOS相关蛋白，可能作为支架 将nNOS与其他蛋白质联系起来。我们最近发现了Capon的相互作用 与突触囊泡蛋白突触素和RAS的新成员Dexrasl 一家人。我们将继续研究卡彭作为桥梁传递 NNOS向突触素生成NO影响突触血管功能 Dexrasl通过影响其下游信号来改变核功能。(3) 较高的肌醇多聚磷酸盐：较高的肌醇多磷酸 具有e的焦磷酸盐：-我们认为可能参与调节的磷酸基团 磷酸盐向蛋白质的转移，可能与突触小泡有关 营业额。我们将扩展我们提纯和克隆IP6的研究 激酶，形成焦磷酸PP-IPs(IP7)。我们将描述 这种酶和一种相关蛋白的功能，PIUS也具有IP6 激活酶活性。我们将通过PP-IP来表征可能的蛋白质磷酸化 5.我们还将完成PP-IPs激酶的纯化和克隆 形成含有两个焦磷酸基团的双PP-IP4

项目成果

Cysteine Metabolism in Neuronal Redox Homeostasis.

• DOI: 10.1016/j.tips.2018.02.007
• 发表时间: 2018-05
• 期刊: Trends in pharmacological sciences
• 影响因子: 13.8
• 作者: Paul BD;Sbodio JI;Snyder SH
• 通讯作者: Snyder SH

D-cysteine is an endogenous regulator of neural progenitor cell dynamics in the mammalian brain.

D-半胱氨酸是哺乳动物大脑中神经祖细胞动力学的内源性调节剂。

• DOI: 10.1073/pnas.2110610118
• 发表时间: 2021
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Semenza,EvanR;Harraz,MagedM;Abramson,Efrat;Malla,AdarshaP;Vasavda,Chirag;Gadalla,MoatazM;Kornberg,MichaelD;Snyder,SolomonH;Roychaudhuri,Robin
• 通讯作者: Roychaudhuri,Robin

Biliverdin reductase bridges focal adhesion kinase to Src to modulate synaptic signaling.

• DOI: 10.1126/scisignal.abh3066
• 发表时间: 2022-05-10
• 期刊: SCIENCE SIGNALING
• 影响因子: 7.3
• 作者: Vasavda, Chirag;Semenza, Evan R.;Liew, Jason;Kothari, Ruchita;Dhindsa, Ryan S.;Shanmukha, Shruthi;Lin, Anthony;Tokhunts, Robert;Ricco, Cristina;Snowman, Adele M.;Albacarys, Lauren;Pastore, Francesco;Ripoli, Cristian;Grassi, Claudio;Barone, Eugenio;Kornberg, Michael D.;Dong, Xinzhong;Paul, Bindu D.;Snyder, Solomon H.
• 通讯作者: Snyder, Solomon H.

Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade.

• DOI: 10.1016/j.celrep.2015.01.014
• 发表时间: 2015-02-10
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Tyagi R;Shahani N;Gorgen L;Ferretti M;Pryor W;Chen PY;Swarnkar S;Worley PF;Karbstein K;Snyder SH;Subramaniam S
• 通讯作者: Subramaniam S