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：（申请人的摘要） 现代神经科学的核心挑战是了解 神经元通信以及内源性的调节和合成 在正常和病理条件下，大脑中的sigal分子。 与经典的神经递质和神经肽不同，气态一氧化氮（NO） 合成并发行，没有特殊存储的中介， 随后自由越过膜屏障并相对影响目标 通过直接共价键合大距离。虽然没有至关重要 大多数主要神经元功能（包括学习，记忆， 分化和细胞凋亡），由此产生的不取决于其局部 浓度和局部微环境。没有一个可以用作通用的 信号分子和神经保护剂，或作为突出的神经毒性 中间的。病后脑损伤，中风和 神经退行性疾病与突出的疾病直接相关 否生产过多。没有合成酶（NOS）被接受为唯一的否来源 神经系统中的合成，尽管NOS抑制剂显示出希望 防止过量生产的药理工具， 有效性是有争议的。但是，由于所有这些病理是 通常与组织酸化有关，我们提出了一个替代方案 神经系统中无形成的NOS独立机制， 酸化和还原的亚硝酸盐的非酶NO合成 微环境。该合成途径可能解释了多余的O 这些病理。亚硝酸盐本身是无氧化和 可以积聚在特定的细胞和组织中。此外，由于 相对较高的内源亚硝酸盐浓度和实质性pH值 与神经元活动相关的瞬态，该途径可能是 在正常条件下的补品无生产机制。这 该提案的长期目标是分析分布和 NO的这种免费NOS依赖性途径的功能意义 神经组织中的形成，具体来说是硝化的 （无产生）神经元及其突触后靶标。分离酶促和 非酶NO合成我们将使用选择性的NOS抑制剂和 对这两种途径涉及的主要代谢产物的微化学分析。 微电极电气记录和PH1测量将进一步提供 单个硝酸神经元的功能性化合物化。因此，重要 我们可以理解这种气体的综合，可以取得收益 大脑中的使者。这项工作也将有助于我们的理解 在正常和病理条件下的神经功能。