NOS-INDEPENDENT NO PRODUCTION IN THE NERVOUS SYSTEM

神经系统中不产生 NOS 独立性

• 批准号: 6188311
• 负责人: LEONID L MOROZ
• 金额: $ 17.76万
• 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/6188311
• 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） 现代神经科学的一个核心挑战是理解神经机制 神经元间通讯以及内源性神经元的调节和合成 在正常和病理条件下，大脑中的信号分子。 与经典的神经递质和神经肽不同，气态一氧化氮 (NO) 无需特殊存储中介即可合成和释放， 随后自由穿过膜屏障并相对影响目标 通过直接共价键合，距离很远。尽管 NO 对于 大多数主要神经元功能（包括学习、记忆、 分化和凋亡），所产生的 NO 作用取决于其局部 浓度和局部微环境。 NO 既可以充当多才多艺的角色 信号分子和神经保护剂，或作为突出的神经毒性剂 中间的。缺血后脑损伤、中风和 神经退行性疾病与显着的疾病直接相关 NO. 生产过剩一氧化氮合酶（NOS）被认为是一氧化氮的唯一来源 神经系统中的合成，并且，尽管 NOS 抑制剂显示出作为 防止NO过量产生的药理学仪器，其 有效性存在争议。然而，由于所有这些病症都是 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 形成的独立于 NOS 的机制 在酸化和还原条件下由亚硝酸盐非酶促合成 NO 微环境。该合成途径可能解释了过量的 O 这些病症。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 相对较高的内源性亚硝酸盐浓度和较高的 pH 值 与神经元活动相关的瞬变，该途径可能是 正常条件下产生补品 NO 的附加机制。这 该提案的长期目标是分析分布和 这种不依赖 NOS 的互补途径的功能意义 神经组织中的形成，特别是表征氮 （NO 产生）神经元及其突触后靶标。分离酶和 非酶促无合成我们将使用选择性 NOS 抑制剂和 对这两个途径涉及的主要代谢物进行微化学分析。 微电极电记录和 pH1 测量将提供进一步的帮助 单个氮质神经元的功能表征。因此，显着 我们可以加深对这种气态合成的理解 大脑中的信使。这项工作也将有助于我们理解 正常和病理条件下的神经功能。