ROLE OF HORMONES IN THE PROCESSING OF NEURONAL PEPTIDES

激素在神经元肽加工中的作用

• 批准号: 3227537
• 负责人: AYALLA BARNEA
• 金额: $ 18.33万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-06-01 至 1993-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3227537
• 关键词: adrenalectomy; atomic absorption spectrometry; brain mapping; copper; corticosteroids; cyclic AMP; histidine; homeostasis; hormone regulation /control mechanism; laboratory rat; median eminence; metal metabolism; neural information processing; neuroendocrine system; neurons; neuropeptide receptor; neuropeptides; norepinephrine; potassium; prostaglandin E; radioimmunoassay; secretion; steroid hormone; veratrum alkaloid

Our goals are to elucidate the mechanisms underlying release of LH- releasing hormone (LHRH) from hypothalamic neurons and its regulation by steroids. Our studies led to the formulation of this working hypothesis: Copper (Cu), co-released with norepinephrine (NE) or a-amidated peptides, modulates LHRH relaease; one such action of Cu is the amplification of prostaglandin E2 (PGE2) stimulation of LHRH release. Adrenal steroids exert a positive input on LHRH relaease in the maturing male rat, by regulating the plasma-membrane machinery involved in the process of Cu- amplified PGE2 (Cu/PGE2) stimulation of LHRH release and by regulating Cu release from neurons impinging on the LHRH neuron. S.A.1 is to elucidate the mechanism(s) by which Cu modulates LHRH release; using explants of the median eminence as a model. We will investigate (i) whether and how a CuNE complex mixture stimulates LHRH release; (ii) whether Cu amplification of PGE2 stimulation of LHRH release is a result of Cu interaction with the opioid receptor and/or Cu inhibition of cAMP efflux. S.A.2. is to elucidate the mechanism(s) underlying adrenal regulation of LHRH release in the maturing male rat; specifically Cu/PGE2- stimulated release. We will (i) characterize the ontogeny of the positive feedback of adrenals steroids on LHRH release and identify the regulatory steroid; (ii) examine the specificity of steroid action on Cu/PGE2 -stimulated release of LHRH by examining the effects on CuHis-, veratridine- and K- induced release; and (iii) study the effect of steroids on the kinetic parameters of Cu and PGE2 interactive sites ad on uptake and release of 67-Cu in various brain regions. S.A3. is to elucidate the biochemical mechanisms underlying Cu homeostasis in the hyothalamus; uptake, release, and intracellular processing. We will (i) further establish the process of 67-Cu release, using veratridine (Na-influx) induced release as a model; (ii) analyse the kinetics of 67-Cu uptake into the releasable pool of Cu; and (iii) study the intracellular processing of newly taken-up CuHis, specifically ligand exchange of the His. Understanding the mechanisms underlying Cu action on the LHRH neuron and steroid regulation of LHRH release in teh maturing male, will provide insight into integrative regulatory processes in the brain and into developmental and hormonally regulated brain functions.

我们的目标是阐明潜在的机制释放的 下丘脑神经元LH-释放激素及其与 类固醇的调节。 我们的研究导致了这个公式 工作假设：铜（Cu），与去甲肾上腺素共同释放 (NE)或α-酰胺化肽调节LHRH释放;一种这样的 铜的作用是放大前列腺素E2（PGE 2） 刺激LHRH释放。 肾上腺类固醇发挥积极作用， 输入对成熟雄性大鼠LHRH释放的影响，通过调节 参与铜-锌过程的质膜机制， PGE 2（Cu/PGE 2）对LHRH释放的刺激作用增强， 调节与LHRH接触的神经元的Cu释放 neuron. S.A.1旨在阐明Cu 调节LHRH释放;使用正中隆起的外植体 做模特 我们将调查（i）是否以及如何一个CuNE 复杂的混合物刺激LHRH的释放;（ii）是否铜 PGE 2刺激LHRH释放的放大是 Cu与阿片受体的相互作用和/或Cu抑制 cAMP流出。 S.A.2.是为了阐明 肾上腺对成熟雄性大鼠LHRH释放的调节; 特别是Cu/PGE 2刺激的释放。 我们将（i）描述 肾上腺激素正反馈的个体发生 LHRH释放和识别调节类固醇;（ii）检查 甾体激素对Cu/PGE_2刺激下释放的特异性 LHRH通过检查对CuHis-，藜芦碱-和K-的影响， 诱导释放;和（iii）研究类固醇对 Cu和PGE 2相互作用位点对吸收的动力学参数 以及在不同脑区释放67-Cu。 S.A3.是 阐明铜稳态的生化机制 吸收、释放和细胞内加工。 我们将（i）进一步建立67-Cu释放的过程，使用 作为模型的藜芦碱（Na-流入）诱导的释放;（ii）分析 67-Cu吸收到可释放的Cu库中的动力学;以及（iii） 研究新摄取的CuHis的细胞内加工， 特别是His的配体交换。 了解铜对LHRH作用的机制 成熟过程中LHRH释放神经元和类固醇调节 男性，将提供深入了解综合监管过程， 进入发育和神经调节的大脑 功能协调发展的