Neuropeptide Regulation Vasopressin/Oxytocin Secretion

神经肽调节加压素/催产素分泌

• 批准号: 7047737
• 负责人: CELIA D SLADEK
• 金额: $ 24.78万
• 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 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7047737
• 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.

性状（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各种 神经递质和神经肽传入到视上神经， 下丘脑的室旁核。这些传入神经中有许多是共同定位的 并共同释放多种神经活性物质。在评价对下列问题的答复时， 在A1儿茶酚胺神经元中共定位的试剂（例如去甲肾上腺素，ATP， 神经肽Y（NPY）和P物质（SP），我们发现了差异的证据， 增强激素释放的这些物质，以及一个有效的， 特别是，联合暴露于SP和ATP或 NPY和苯肾上腺素（PE，α肾上腺素能受体激动剂）导致 VP和OT释放的协同刺激。本提案的目标 目的是确定NPY和SP在诱发VP和OT中的相对重要性 对生理挑战的反应，并阐明细胞机制 负责这些协同反应。因为A1通路传递 关于VP和OT的血压/容量中度降低的信息 神经元，SP和NPY可能是重要的，这种生理反应。目标1将 检验A1终末释放SP和NPY是必需的假设 用于激活VP神经元以响应低血压。的影响 单侧视上核（SON）注射SP和NPY受体 将在出血后评估拮抗剂对SON中Fos表达的影响， 急性渗透刺激。目标2将评估细胞机制 负责共同暴露于SP/ATP和NPY/PE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;决定蛋白质的作用 激酶C和IP 3介导的Ca++释放;并评估基因的作用 转录。目的3：验证SP和NPY受体在脑缺血再灌注损伤中的作用 SON中的表达通过刺激A1通路而改变。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/Y 5神经肽Y受体的表达 水剥夺、慢性盐水摄入和出血后的大鼠。目的 4将检验脱水诱导的Y1/Y 5受体增加的假设， SON表达改变VP和OT对NPY的反应。VP和OT响应 将使用从暴露于 长期缺水VP分泌不足或不当 例如直立性低血压和充血性心力衰竭的病理。 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， 病理状态的治疗。

项目成果

Influence of dehydration on the expression of neuropeptide Y Y1 receptors in hypothalamic magnocellular neurons.

脱水对下丘脑大细胞神经元神经肽 Y Y1 受体表达的影响。

• DOI: 10.1210/en.2006-0377
• 发表时间: 2006
• 期刊: Endocrinology.
• 作者: Urban,JaniceH;Leitermann,RandyJ;DeJoseph,MRegina;Somponpun,SuwitJ;Wolak,MichaelL;Sladek,CeliaD
• 通讯作者: Sladek,CeliaD