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.

描述（由申请人提供）：加压素 (VP) 和催产素 (OT) 垂体后叶的分泌是由于多种原因而发生的 神经递质和神经肽传入视上和 下丘脑的室旁核。许多这些传入神经共同定位 并共同释放多种神经活性物质。在评估回应时 共定位于 A1 儿茶酚胺神经元的药物（例如去甲肾上腺素、ATP、 神经肽 Y (NPY) 和物质 P (SP)，我们发现了差异的证据 这些物质可以增强激素的释放，并具有有效的作用 对SP的持续反应。具体来说，联合暴露于 SP 和 ATP 或 NPY 和去氧肾上腺素（PE，一种 α 肾上腺素能受体激动剂）导致 VP 和 OT 释放的协同刺激。当前提案的目标 确定 NPY 和 SP 在引发 VP 和 OT 中的相对重要性 对生理挑战的反应并阐明细胞机制 负责这些协同反应。由于 A1 途径传输 向 VP 和 OT 提供有关血压/容量适度下降的信息 神经元、SP 和 NPY 可能对这种生理反应很重要。目标1将 检验需要从 A1 终端释放 SP 和 NPY 的假设 用于激活 VP 神经元以应对低血压。的效果 单侧视上核 (SON) 注射 SP 和 NPY 受体 SON 中 Fos 表达的拮抗剂​​将在出血或 急性渗透刺激。目标 2 将评估细胞机制 负责对 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 Ca++ 释放；并评估基因的作用 转录。目标 3 将检验 SP 和 NPY 受体的假设 SON 中的表达通过刺激 A1 途径而改变。蛋白质印迹， 免疫细胞化学和原位杂交将用于评估 神经激肽 3 速激肽受体和 Y1/Y5 NPY 受体在 大鼠缺水、长期摄入盐水和​​出血后。目的 4 将检验脱水诱导 Y1/Y5 受体增加的假设 SON 中的表达改变 VP 和 OT 对 NPY 的反应。副总裁和 OT 回应 将使用从暴露于 NPY 的大鼠获得的 HNS 外植体进行评估 长期缺水。 VP 分泌不足或不适当会导致 体位性低血压和充血性心力衰竭等病理。 了解特定神经递质在传递血流动力学中的作用 VP 和 OT 神经元的信息是操纵系统的核心 治疗病理状况。