Secretin/vip Family Receptors

促胰液素/vip家族受体

• 批准号: 6980303
• 负责人: Ted B Usdin
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6980303
• 关键词: cell surface receptors; hormone receptor; neuroanatomy; neuroendocrine system; neuropeptides; neurotransmitter receptor; pain; parathyroid hormones; pituitary hormones; protein biosynthesis; protein structure function; secretin

Neurotransmitter receptors provide access to neuronal circuits for investigation of their biology, and potentially for therapeutic intervention. Peptides have effects on G-protein coupled receptors that are often relatively long lasting and they may have a modulatory role. These subtle effects may be relevant to the basis or treatment of mental illness. We are studying a family of G-protein coupled receptors (referred to as the secretin-VIP, B, or type II family) that is structurally distinct from the majority of G-protein coupled receptors (rhodopsin- or beta-adrenergic-like). Recently we have focused on the parathyroid hormone 2 (PTH2) receptor, which we identified in a screen for novel central nervous system expressed polypeptide receptors. Our initial studies of the human PTH2 receptor showed that it was activated by parathyroid hormone (PTH). Mapping the PTH2 receptor's anatomical distribution revealed expression within brain areas not normally exposed to circulating peptides, such as PTH. Furthermore, we found that PTH poorly activates the rat PTH2 receptor. Using selective activation of the PTH2 receptor as an assay we purified a previously unknown 39 amino acid peptide from bovine hypothalamus. This peptide, which we named tuberoinfundibular peptide of 39 residues (TIP39), activates PTH2 receptors from human, rat and zebrafish and does not activate PTH1 receptors. Both rat and zebrafish PTH2 receptors are much more effectively activated by TIP39 than PTH, supporting the suggestion that a TIP39 homologue is their natural ligand. We have now mapped the neuroanatomical distribution of TIP39 synthesizing neurons and their projections, which has generated hypotheses about the physiological function of TIP39. We are currently testing hypotheses for the biological role (s) of TIP39 and the PTH2 receptor derived from detailed mapping of the receptor and peptides distributions that we performed. We have obtained data that supports a role for TIP39 and the PTH2 receptor in modulating pain perception and shown that it has similar effects to antidepressant and anxiolytic drugs in some animal behavior assays. We, and other investigators, also have preliminary data supporting a role for TIP39 and the PTH2 receptor in pituitary hormone release. We are attempting to develop mice with PTH2 receptor and TIP39 null phenotypes to aid in elucidating the function of this peptide-receptor system. The Mammalian Gene Collection project is a trans-NIH effort to collect and distribute to the public full-length cDNA clones for all human and mouse genes. We are contributing to this effort by working on methods to improve generation of high quality cDNA libraries from small amounts of tissue, and have contributed several libraries to the project that have a high yield of useful clones.

神经递质受体可访问神经元回路以研究其生物学，并有可能进行治疗干预。肽对G蛋白偶联受体的影响通常相对较长，并且可能具有调节作用。这些微妙的影响可能与精神疾病的基础或治疗有关。我们正在研究一个G蛋白偶联受体（称为Secralin-VIP，B或II型家族）的家族，该家族在结构上与大多数G蛋白偶联受体（Rhopopsin-或β-肾上腺肾上腺素能样）不同。 。最近，我们专注于甲状旁腺激素2（PTH2）受体，我们在新型的中枢神经系统表达多肽受体的屏幕中鉴定出来。我们对人PTH2受体的最初研究表明，它是由甲状旁腺激素（PTH）激活的。映射PTH2受体的解剖分布显示在通常不暴露于循环肽（例如PTH）的大脑区域内表达表达。此外，我们发现PTH激活了大鼠PTH2受体。使用PTH2受体的选择性激活作为测定，我们从牛下丘脑纯化了先前未知的39个氨基酸肽。我们将这种肽命名为39个残基（TIP39）的结核fundibular肽，它激活了来自人，大鼠和斑马鱼的PTH2受体，并且不激活PTH1受体。大鼠和斑马鱼PTH2受体都比PTH更有效地激活了TIP39，这支持了TIP39同源物是其天然配体的建议。现在，我们已经绘制了TIP39合成神经元及其投影的神经解剖学分布，该分布产生了有关TIP39生理功能的假设。目前，我们正在测试tip39的生物学作用的假设以及我们执行的受体和肽分布的详细映射得出的PTH2受体。我们获得了支持TIP39和PTH2受体在调节疼痛感知中的作用的数据，并表明它在某些动物行为分析中与抗抑郁药和抗焦虑药具有相似的作用。我们和其他研究人员还具有初步数据，该数据支持TIP39和PTH2受体在垂体激素释放中的作用。我们正在尝试开发使用PTH2受体和TIP39 NULL表型的小鼠，以帮助阐明该肽受体系统的功能。 哺乳动物基因收集项目是一种跨NIH的努力，旨在为所有人类和小鼠基因收集和分发给公共全长cDNA克隆。我们通过努力从少量组织中改善高质量cDNA文库的产生的方法来为这一努力做出贡献，并为该项目贡献了几个具有有用克隆产量的项目。