Neuropeptide Regulation Vasopressin/Oxytocin Secretion

神经肽调节加压素/催产素分泌

• 批准号: 6710592
• 负责人: CELIA D SLADEK
• 金额: $ 25.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6710592
• 关键词: biological signal transduction; body water dehydration; calcium ion; fos protein; genetic transcription; hemorrhage; hormone biosynthesis; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; inositol phosphates; intermolecular interaction; laboratory rat; neurohypophysis; neurons; neuropeptide Y; neuropeptide receptor; osmosis; oxytocin; protein kinase C; receptor expression; secretion; substance P; supraoptic nucleus; vasopressins; western blottings

DESCRIPTION (provided by applicant): Vasopressin (VP) and oxytocin (OT) secretion from the posterior pituitary occurs as a result of a variety of neurotransmitters and neuropeptide afferents to the supraoptic and paraventricular nuclei in the hypothalamus. Many of these afferents co-localize and co-release multiple neuroactive substance. In evaluating the responses to agents colocalized in the A1 catecholamine neurons (e.g. norepinephrine, ATP, neuropeptide Y (NPY), and substance P (SP), we found evidence for differential potentiation of hormone release by these substances as well as a potent and sustained response to SP. Specifically, combined exposure to SP and ATP or to NPY and phenylephrine (PE, an alpha adrenergic receptor agonist) resulted in synergistic stimulation of VP and OT release. The goals of the current proposal are to determine the relative importance of NPY and SP in eliciting VP and OT responses to physiological challenges and to elucidate the cellular mechanisms responsible for these synergistic responses. Since the A1 pathway transmits information about moderate decreases in blood pressure/volume to the VP and OT neurons, SP and NPY may be important to this physiological response. Aim 1 will test the hypothesis that release of SP and NPY from A1 terminals is required for activation of VP neurons in response to hypotension. The effect of unilateral supraoptic nucleus (SON) injections of SP and NPY receptor antagonists on Fos expression in SON will be assessed following hemorrhage or an acute osmotic stimulus. Aim 2 will evaluate the cellular mechanisms responsible for the synergistic responses to co-exposure to SP/ATP and NPY/PE. Explants of the hypothalamo-neurohypophyseal system will be used to: identify the receptor types required for synergism; determine the roles of protein kinase C and IP3-mediated Ca++ release; and evaluate the role of gene transcription. Aim 3 will test the hypothesis that SP and NPY receptor expression in SON is altered by stimulation of the A1 pathway. Western blots, immunocytochemistry, and in situ hybridization will be used to assess the expression of the neurokinin 3 tachykinin receptor and Y1/Y5 NPY receptors in rats following water deprivation, chronic saline ingestion, and hemorrhage. Aim 4 will test the hypothesis that dehydration-induced increases in Y1/Y5 receptor expression in SON alter the VP and OT response to NPY. The VP, and OT response to NPY will be evaluated using HNS explants obtained from rats exposed to chronic water deprivation. Inadequate or inappropriate VP secretion contributes to pathologies such as orthostatic hypotension and congestive heart failure. Understanding the role of specific neurotransmitters in relaying hemodynamic information to the VP and OT neurons is central to manipulating the system for treatment of pathological conditions.

说明(申请人提供)：加压素(VP)和催产素(OT) 脑下垂体后叶的分泌物是由多种 视上区和视网膜区的神经递质和神经肽传入 下丘脑室旁核。其中许多传入细胞共同定位 并共同释放多种神经活性物质。在评估对以下方面的反应时 共同定位于A1儿茶酚胺神经元的药物(如去甲肾上腺素、ATP、 神经肽Y(NPY)和P物质(SP)，我们发现了区分 这些物质对激素释放的促进作用以及一种有效的 对SP的持续响应。具体地说，SP和ATP的联合暴露或 NPY和苯肾上腺素(PE，一种α肾上腺素能受体激动剂)导致 协同刺激VP和OT的释放。当前提案的目标 是为了确定NPY和SP在诱发VP和OT中的相对重要性 对生理挑战的反应并阐明其细胞机制 负责这些协同反应。由于A1通路传输 关于VP和OT的血压/容量适度下降的信息 神经元、SP和NPY可能在这种生理反应中起重要作用。目标1将 检验A1端需要释放SP和NPY的假设 用于激活VP神经元以应对低血压。的影响 单侧视上核(SON)注射SP和NPY受体 对SON中Fos表达的拮抗剂将在出血后或 一种急性渗透性刺激。目标2将评估细胞机制 负责SP/ATP和NPY/PE共同暴露的协同反应。 下丘脑-神经垂体系统的外植体将用于： 协同作用所需的受体类型；确定蛋白质的作用 激酶C和IP3介导的钙释放；并评价基因的作用 抄写。目标3将检验SP和NPY受体的假设 刺激A1通路可改变SON的表达。西方印迹图， 免疫细胞化学和原位杂交将被用来评估 神经激肽3、速激肽受体和Y1/Y5 NPY受体的表达 缺水、长期摄入生理盐水和出血后的大鼠。目标 4将检验脱水导致Y1/Y5受体增加的假设 SON的表达改变了VP和OT对NPY的反应。副总裁和加班反应 TO NPY将使用从暴露于 长期缺水。VP分泌不足或不适当是导致 直立性低血压和充血性心力衰竭等病理改变。 了解特定神经递质在传递血流动力学中的作用 传递给VP和OT神经元的信息是操纵系统的核心 病理情况的治疗。