TELEOST PARATHYROID RECEPTOR BIOLOGY

最新甲状旁腺受体生物学

• 批准号: 2443889
• 负责人: DAVID Alan RUBIN
• 金额: $ 2.99万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2443889
• 关键词: biochemical evolution; hormone receptor; parathyroid hormones; protein structure function; species difference

The PTH/PTHrP receptor (PPR) mediates the biological actions of two peptide hormones, PTH and PTH-related peptide (PTHrP). PTH is the major regulator of mammalian mineral ion homeostasis. PTHrP and the common PPR are both crucial for normal development, since the disruption of either gene in mice results in lethal phenotypes with widespread abnormalities of endochondral bone formation. These "knockout" studies indicated furthermore that the common PPR is essential for mediating the functions of PTH and PTHrP, and that no other receptor can serve as a substitute. However, a novel, PTH-specific receptor (PTH2R) with significant amino acid sequence homology to the PPR was isolated from mammals, but its biological importance is not yet known. Interestingly, cDNAs encoding fish PTH2R homologs were recently isolated also from catfish and zebrafish cDNA libraries. If these novel receptors are activated only by PTH, as the mammalian PTH2R homolog, these findings suggest that a PTH-like molecule exists also in vertebrate species that do not have parathyroid glands and that PTH expression occurs in species lacking distinct parathyroid glands. In the current proposal, I will therefore study the coevolution and function of two closely related G protein-coupled PTH-/PTHrP-receptors and their two distinct ligands. The resulting findings are expected to provide evidence for possible function(s) of both ligands and both receptors in nonmammalian vertebrates, and may provide further clues for biological role(s) in mammals that are distinct from those required for the control of mineral ion homeostasis.

PTH/PTHrP 受体 (PPR) 介导两种生物作用 肽激素、PTH 和 PTH 相关肽 (PTHrP)。 PTH是主要的 哺乳动物矿物离子稳态的调节剂。 PTHrP 和普通 PPR 两者对于正常发展都至关重要，因为其中任何一个的破坏 小鼠体内的基因导致致命的表型，普遍存在异常 软骨内骨形成。这些“淘汰”研究表明 此外，共同的 PPR 对于调解职能至关重要 PTH 和 PTHrP，并且没有其他受体可以替代。 然而，一种新型 PTH 特异性受体 (PTH2R) 具有显着的氨基 与PPR同源的酸序列是从哺乳动物中分离出来的，但其 生物学重要性尚不清楚。有趣的是，编码鱼的cDNA 最近还从鲶鱼和斑马鱼 cDNA 中分离出 PTH2R 同源物 图书馆。如果这些新受体仅由 PTH 激活，则 哺乳动物 PTH2R 同源物，这些发现表明 PTH 样分子 也存在于没有甲状旁腺的脊椎动物中 PTH 表达发生在缺乏独特甲状旁腺的物种中。 因此，在当前的提案中，我将研究共同进化和 两个密切相关的 G 蛋白偶联 PTH-/PTHrP-受体的功能 它们的两个不同的配体。由此产生的结果预计将提供 两种配体和两种受体的可能功能的证据 非哺乳动物脊椎动物，并可能为生物学提供进一步的线索 在哺乳动物中的作用与控制所需的作用不同 矿物质离子稳态。