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.

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