The 7-34-fragment of human hypercalcemia factor is a partial agonist/antagonist for parathyroid hormone-stimulated cAMP production.
The 7-34-fragment of human hypercalcemia factor is a partial agonist/antagonist for parathyroid hormone-stimulated cAMP production.
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人高钙血症因子的 7-34 片段是甲状旁腺激素刺激的 cAMP 产生的部分激动剂/拮抗剂。
DOI：
10.1210/endo-122-6-3008
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发表时间：
1988
期刊：
影响因子：
4.8
通讯作者：
Michael Rosenblatt
中科院分区：
文献类型：
--
作者：
Roberta L. McKee;Mark E. Goldman;Michael P. Caulfield;P. DeHAVEN;J. Levy;Ruth F. Nutt;Michael Rosenblatt
人高钙血症因子（hHCF）的N端片段hHCF-（1-34）NH 2在体内外均具有与PTH相似的生物活性。因为它与PTH受体相互作用，并且在某些系统中比PTH更有效，所以hHCF序列可以为设计有效和选择性的PTH和hHCF拮抗剂提供有趣的线索。基于[Tyr 34] bPTH-（7-34）NH 2的拮抗活性，我们合成了相应的hHCF片段hHCF-（7 - 34）NH 2，并对其体外性质进行了研究。在骨源性大鼠骨肉瘤细胞系ROS 17/2.8中，hHCF-（7-34）NH 2和[Tyr 34]bPTH-（7-34）NH 2对放射性标记的PTH结合的抑制是等效的。相比之下，hHCF-（7-34）NH 2抑制PTH刺激的cAMP产生的效力是[Tyr 34]bPTH-（7-34）NH 2的8倍。hHCF-（7-34）NH 2也抑制牛肾皮质膜中PTH结合和PTH刺激的腺苷酸环化酶活性：hHCF-（7-34）NH 2和[Tyr 34]bPTH-（7-34）NH 2在该系统中是等效的。此外，hHCF-（7-34）NH 2在两个系统中以相似的抑制常数拮抗hHCF-（1-34）NH 2的作用。然而，与PTH类似物不同，hHCF-（7-34）NH 2（8 μ M）是一种弱的部分激动剂，在ROS细胞中产生2.4倍的cAMP增加（最大反应的5%）。该相同系统还检测另一种PTH部分激动剂/拮抗剂[Nle 8，18 Tyr 34]bPTH-（3-34）NH 2的激动作用。这些结果表明，hHCF-（7-34）NH 2与PTH受体的相互作用很大程度上基于与PTH不同源的区域，并表明ROS 17/2.8细胞系统可用于体外鉴定PTH和hHCF类似物的弱激动作用。
The N-terminal fragment of human hypercalcemia factor (hHCF), hHCF-(1-34)NH2, has bioactivities similar to PTH in vitro and in vivo. Because it interacts with PTH receptors and is more potent than PTH in some systems, the hHCF sequence may provide interesting leads for the design of potent and selective PTH and hHCF antagonists. Based on the antagonist activity of [Tyr34]bovine PTH-(7-34)NH2 [( Tyr34]bPTH-(7-34)NH2), we synthesized the corresponding fragment of hHCF, hHCF-(7-34)NH2 and examined its properties in vitro. In the bone-derived rat osteosarcoma cell line ROS 17/2.8, hHCF-(7-34)NH2 and [Tyr34]bPTH-(7-34)NH2 were equipotent for inhibition of radiolabeled PTH-binding. In contrast, hHCF-(7-34)NH2 was 8-fold more potent that [Tyr34]bPTH-(7-34)NH2 for inhibiting PTH-stimulated cAMP production. hHCF-(7-34)NH2 also inhibited PTH-binding and PTH-stimulated adenylate cyclase activity in bovine renal cortical membranes: hHCF-(7-34)NH2 and [Tyr34]bPTH-(7-34)NH2 were equipotent in this system. In addition, hHCF-(7-34)NH2 antagonized hHCF-(1-34)NH2 action in both systems with similar inhibition constants. However, unlike the PTH analogue, hHCF-(7-34)NH2 (8 microM) was a weak partial agonist, producing a 2.4-fold increase in cAMP (5% of the maximal response) in ROS cells. This same system also detects agonism for [Nle8, 18Tyr34]bPTH-(3-34)NH2, another PTH partial agonist/antagonist. These results demonstrate that hHCF-(7-34)NH2 interacts with PTH receptors based in large part on the region which is not homologous to PTH, and suggest the utility of the ROS 17/2.8 cell system for identifying weak agonism of PTH and hHCF analogues in vitro.