NOS-INDEPENDENT NO PRODUCTION IN THE NERVOUS SYSTEM

神经系统中不产生 NOS 独立性

• 批准号: 6394221
• 负责人: LEONID L MOROZ
• 金额: $ 17.35万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-24 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6394221
• 关键词: Mollusca; biological signal transduction; electrophysiology; neurochemistry; neurons; neurophysiology; neurotransmitter biosynthesis; nitric oxide; nitrites; pathologic process

DESCRIPTION: (Applicant's Abstract) A central challenge to modern neuroscience is to understand mechanisms of interneuronal communications, and the regulation and synthesis of endogenous sigal molecules in the brain, in both normal and pathological conditions. Unlike classical neurotransmitters and neuropeptides, gaseous nitric oxide (NO) is synthesized and released without the intermediary of special storage, subsequently freely crossing membrane barriers and affecting targets relatively large distances away, by direct covalent bonding. Although NO is crucial for most of the major neuronal functions (including learning, memory, differentiation and apoptosis), the resulting NO action depends on its local concentrations and the local microenvironment. NO can act either as a versatile signal molecule, and neuroprotective agent, or as a prominent neurotoxic intermediate. The development of postschemic brain injury, stroke, and neurodegenerative diseases are directly associated with a prominent overproduction of NO. NO synthase (NOS) is accepted as the only source of NO synthesis in the nervous system, and, although NOS inhibitors show promise as pharmacological instruments to prevent overproduction of NO, their effectiveness is controversial. However, since all these pathologies are generally associated with tissue acidification, we propose an alternative NOS-independent mechanism of NO formation in the nervous system, the non-enzymatic NO synthesis from nitrites in acidified and reducing micro-environments. This synthetic pathway may account for the excess O in these pathologies. Nitrites themselves are the main product of NO oxidation and can be accumulated in specific cells and tissues. Furthermore, due to the relatively high endogenous nitrite concentrations and the substantial pH transients associated with neuronal activity, this pathway is likely an additional mechanism for tonic NO production under normal conditions. The long-term objectives of this proposal are to analyze the distribution and functional significance of this complimentary NOS-independent pathway of NO formation in the nervous tissues, and, specifically, to characterize nitregic (NO producing) neuron and their postsynaptic targets. To separate enzymatic and non-enzymatic No synthesis we will use selective NOS inhibitors and microchemical analysis of major metabolites involved in these two pathways. Microelectrode electrical recording and pH1 measurements will provide further functional chracterization of individual nitregic neurons. Thus, significant gains can be made in our understanding of the synthesis of this gaseous messenger in the brain. This work will also contribute to our understanding of the neural functions in normal and pathological conditions.

描述：(申请人摘要) 现代神经科学面临的一个中心挑战是理解 神经元间通讯与内源性神经递质的调节和合成 大脑中的信号分子，在正常和病理条件下都是如此。 与经典的神经递质和神经肽不同，气态一氧化氮(NO) 在没有特殊存储中介的情况下合成和释放， 随后相对自由地跨过膜屏障和影响目标 距离很远，通过直接共价键。尽管NO对 大多数主要的神经元功能(包括学习、记忆、 分化和凋亡)，由此产生的NO作用依赖于其局部 浓度和当地的微环境。No既可以充当多面手，也可以充当 信号分子，神经保护剂，或作为一种突出的神经毒性 中级的。脑缺血后损伤、卒中和 神经退行性疾病与一种突出的 NO.生产过剩。一氧化氮合成酶(NOS)被认为是一氧化氮的唯一来源 神经系统的合成，尽管一氧化氮合酶抑制剂显示出作为 防止NO过量产生的药理工具，他们的 有效性是有争议的。然而，由于所有这些病理都是 通常与组织酸化有关，我们提出了一种替代方案 神经系统中NO形成的非依赖于NO的机制 酸化还原条件下亚硝酸盐非酶催化合成NO 微环境。这种合成途径可能是体内过量氧的原因。 这些病态。亚硝酸盐本身是NO氧化的主要产物， 可以在特定的细胞和组织中积累。此外，由于 相对较高的内源亚硝酸盐浓度和相当高的pH 与神经元活动相关的瞬时信号，这一途径可能是一种 正常情况下产生紧张性NO的额外机制。这个 这项提案的长期目标是分析分布和 这一互补的一氧化氮合酶非依赖性NO途径的功能意义 在神经组织中的形成，具体地说，表征亚硝酸根 (产生NO的)神经元及其突触后靶点。分离酶制剂和酶制剂的研究 非酶NO合成我们将使用选择性一氧化氮合酶抑制剂和 对这两个途径中涉及的主要代谢物进行微量化学分析。 微电极电记录和PH1测量将进一步提供 单个亚硝酸神经元的功能特征。因此，意义重大 我们可以在理解这种气体的合成方面取得进展 大脑中的信使。这项工作也将有助于我们对 神经在正常和病理状态下的功能。