NOS-INDEPENDENT NO PRODUCTION IN THE NERVOUS SYSTEM

神经系统中不产生 NOS 独立性

• 批准号: 6540159
• 负责人: LEONID L MOROZ
• 金额: $ 17.85万
• 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/6540159
• 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核心挑战是理解神经元的机制。 神经元间通讯，以及内源性 在正常和病理条件下，大脑中的信号分子。 与传统的神经递质和神经肽不同，气态一氧化氮（NO） 合成和释放，而不需要特殊的储存， 随后自由穿过膜屏障并相对影响靶点 通过直接的共价键连接。虽然NO对于 大多数主要的神经元功能（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既可以作为一个多功能的 信号分子和神经保护剂，或作为一种突出神经毒性剂 中间体缺血性脑损伤、中风和 神经退行性疾病与突出的 NO合成酶（NOS）是NO的唯一来源 在神经系统中的合成，而且，虽然NOS抑制剂显示出作为 防止NO过度产生的药理学仪器，其 有效性是有争议的。然而，由于所有这些疾病都是 通常与组织酸化有关，我们提出了一种替代方法， 一氧化氮在神经系统中形成的非一氧化氮依赖性机制， 在酸化和还原条件下由亚硝酸盐非酶促合成NO 微环境。这一合成途径可能解释了 这些病理。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。而且因为 相对较高的内源性亚硝酸盐浓度和相当大的pH 与神经元活动相关的瞬变，这一途径可能是一种 在正常条件下的紧张NO生产的额外机制。的 该提案的长期目标是分析分布情况， 这种互补的NO非依赖性途径的功能意义 神经组织中的形成，并且，具体地说， (NO产生）神经元及其突触后靶点。分离酶和 非酶促NO合成我们将使用选择性NOS抑制剂， 这两种途径中涉及的主要代谢物的微量化学分析。 微电极电记录和pH 1测量将提供进一步的 单个氮区神经元的功能表征。因此， 在我们对这种气体的合成的理解中， 大脑中的信使这项工作也将有助于我们了解 正常和病理状态下的神经功能。

项目成果

NSF workshop report: discovering general principles of nervous system organization by comparing brain maps across species.

NSF 研讨会报告：通过比较不同物种的大脑图谱发现神经系统组织的一般原理。

• DOI: 10.1002/cne.23568
• 发表时间: 2014
• 期刊: The Journal of comparative neurology
• 作者: Striedter,GeorgF;Belgard,TGrant;Chen,Chun-Chun;Davis,FredP;Finlay,BarbaraL;Güntürkün,Onur;Hale,MelinaE;Harris,JulieA;Hecht,ErinE;Hof,PatrickR;Hofmann,HansA;Holland,LindaZ;Iwaniuk,AndrewN;Jarvis,ErichD;Karten,Harvey
• 通讯作者: Karten,Harvey

Characterization of novel cytoplasmic PARP in the brain of Octopus vulgaris.

• DOI: 10.1086/bblv222n3p176
• 发表时间: 2012-06
• 期刊: The Biological bulletin
• 作者: De Lisa E;De Maio A;Moroz LL;Moccia F;Mennella MR;Di Cosmo A
• 通讯作者: Di Cosmo A

Phylogenomics meets neuroscience: how many times might complex brains have evolved?

• DOI: 10.1556/abiol.63.2012.suppl.2.1
• 发表时间: 2012
• 期刊: Acta biologica Hungarica
• 作者: Moroz LL

Phylogenomics reveals deep molluscan relationships.

• DOI: 10.1038/nature10382
• 发表时间: 2011-09-04
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Kocot, Kevin M.;Cannon, Johanna T.;Todt, Christiane;Citarella, Mathew R.;Kohn, Andrea B.;Meyer, Achim;Santos, Scott R.;Schander, Christoffer;Moroz, Leonid L.;Lieb, Bernhard;Halanych, Kenneth M.
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Aplysia.

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• DOI: 10.1016/j.cub.2010.11.028
• 发表时间: 2011-01-25
• 期刊: CURRENT BIOLOGY
• 影响因子: 9.2
• 作者: Moroz, Leonid L.