Neurochemical Actions of Psychotropic Drugs

精神药物的神经化学作用

• 批准号: 9233780
• 负责人: SOLOMON H. SNYDER
• 金额: $ 86.03万
• 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 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233780
• 关键词: AMPA Receptors; Absence Epilepsy; Address; Affect; Amino Acids; Anabolism; Area; Aspartate; Binding; Biological Assay; Brain; Calcium; Cloning; Communication; Crossbreeding; Cystathionine; Cystathionine beta-Synthase; Cysteine; Cysteine Desulfhydrase; D-Amino Acid Dehydrogenase; DLG4 gene; Deaminase; Dominant-Negative Mutation; Drug effect disorder; Enzymes; Generations; Genetic Transcription; Glutamate Agonist; Glutamate Receptor; Glutamates; Grant; High Pressure Liquid Chromatography; Huntington Disease; Huntington gene; Hydrogen Sulfide; Isomerism; Knock-out; Knockout Mice; Ligands; Link; Luciferases; Maps; Mediating; Membrane; Modeling; Monitor; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; Neuromodulator; Nitric Oxide; Obesity; Pathologic; Patients; Phenotype; Physiological; Play; Population; Property; Proteins; Psychotropic Drugs; Regulation; Research; Research Support; Role; Serine; Signal Transduction; Signaling Molecule; Site; Sp1 Transcription Factor; Staining method; Stains; Supplementation; Synapses; System; Techniques; Tissues; Work; base; disease phenotype; luciferin; mutant; neurochemistry; neuropsychiatric disorder; neurotransmission; novel; public health relevance; racemization; receptor binding; relating to nervous system; serine racemase; stargazin; transmission process

DESCRIPTION (provided by applicant): Our research, supported by this grant over the years, has focused on identifying and characterizing novel neural messenger molecules and their roles in psychotropic drug actions. We propose new studies based on recent advances in this area involving, in particular, gasotransmitters and D-amino acids. Based on our earlier work on NO and CO, we have recently identified hydrogen sulfide (H2S) as a notable signaling molecule. We established its biosynthesis by cystathionine-gamma-lyase (CSE) and cystathionine- beta-synthase (CBS) by demonstrating its depletion with CSE and CBS knockout. We showed that H2S signals by sulfhydrating cysteines in target proteins, analogous to NO acting by nitrosylation. We will map CBS/CSE and their catalytic activity via a novel histochemical stain for H2S generation from cysteine. We will characterize new sulfhydrated targets. Based on our findings regarding CSE's transcriptional induction, we will elucidate the enzyme's turnover under diverse conditions. Recently we discovered a profound depletion of CSE in Huntington's Disease (HD) reflecting mutant huntingtin affecting the CSE transcription factor SP1. Pathophysiologic relevance was evident in the alleviation of the HD phenotype by rescue in cultures and intact mice by cysteine supplementation. We will further characterize cysteine/H2S dynamics in HD mice and neural cultures. The cysteine depletion may also account for the inanition of HD patients. Accordingly, we will also investigate the regulation by CSE of adiposity. We established D-serine as an endogenous agonist for glutamate-NMDA receptors, identifying, cloning and characterizing its biosynthetic enzyme serine racemase (SR). Recently, we discovered that SR can link AMPA and NMDA glutamate transmission. SR binds the AMPA receptor accessory protein stargazin leading to membrane association and SR inhibition. SR also binds PSD-95 from which it is dissociated by NMDA treatment. We will elucidate the physiologic significance of SR in an apparent cross-talk between AMPA and NMDA receptor systems. We recently identified substantial levels of D-cysteine in mammalian brain and other tissues. We have developed a novel sensitive and specific assay for tissue D-cysteine. We will monitor D-cysteine levels in diverse tissues under varying circumstances. We will seek biosynthetic mechanisms for D-cysteine via known or hitherto unidentified enzymes.

描述（由申请人提供）：我们的研究，多年来由该基金支持，一直专注于识别和表征新型神经信使分子及其在精神药物作用中的作用。我们提出了新的研究的基础上，在这一领域的最新进展，特别是，gasotransmitters和D-氨基酸。基于我们早期对NO和CO的研究，我们最近发现硫化氢（H2S）是一种重要的信号分子。我们通过用CSE和CBS敲除证明其耗尽，建立了其通过胱硫醚-γ-裂解酶（CSE）和胱硫醚-β-合酶（CBS）的生物合成。我们发现H2S信号通过巯基化靶蛋白中的半胱氨酸，类似于NO通过亚硝基化作用。我们将映射CBS/CSE和它们的催化活性，通过一种新的组织化学染色H2S生成半胱氨酸。我们将描述新的含硫目标。基于我们的研究结果，关于CSE的转录诱导，我们将阐明酶的营业额在不同的条件下。最近，我们发现在亨廷顿氏病（HD）中CSE的严重缺失，反映了影响CSE转录因子SP1的突变亨廷顿蛋白。病理生理学相关性在通过半胱氨酸补充的培养物和完整小鼠中的拯救来缓解HD表型中是明显的。我们将进一步表征HD小鼠和神经培养物中的半胱氨酸/H2S动力学。半胱氨酸耗竭也可能是HD患者营养不良的原因。因此，我们也将研究CSE对肥胖的调节作用。 我们建立了D-丝氨酸作为谷氨酸-NMDA受体的内源性激动剂，鉴定，克隆和表征其生物合成酶丝氨酸消旋酶（SR）。最近，我们发现SR可以连接AMPA和NMDA谷氨酸传递。SR结合AMPA受体辅助蛋白stargazin，导致膜缔合和SR抑制。SR还结合PSD-95，其通过NMDA处理从PSD-95解离。我们将阐明SR在AMPA和NMDA受体系统之间的明显串扰的生理意义。我们最近发现，在哺乳动物的大脑和其他组织中的D-半胱氨酸的实质性水平。我们已经开发了一种新的组织D-半胱氨酸的灵敏和特异性测定。我们将在不同情况下监测不同组织中的D-半胱氨酸水平。我们将通过已知的或迄今未鉴定的酶来寻找D-半胱氨酸的生物合成机制。