1型甲状旁腺激素（PTH）/PTH相关肽（PTHrP）受体在响应PTH(1-34)的羧基末端截短类似物时激活磷脂酶C。

Type-1 parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptors activate phospholipase C in response to carboxyl-truncated analogs of PTH(1-34).

作者信息

Takasu H, Bringhurst F R

机构信息

Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.

出版信息

Endocrinology. 1998 Oct;139(10):4293-9. doi: 10.1210/endo.139.10.6261.

DOI:10.1210/endo.139.10.6261

PMID:9751512

Abstract

The carboxyl(C)-truncated human (h) PTH (hPTH) analog hPTH(1-31), which activates adenylyl cyclase (AC), but not protein kinase C, in rat osteosarcoma cells, exerts an anabolic effect on rat bone in vivo similar to that of hPTH(1-34). It has been proposed, therefore, that this action of PTH(1-34) is mediated exclusively by stimulation of AC via the rat type-1 PTH/PTH-related peptide (PTHrP) receptor (PTH1R). To determine whether this selective signaling pattern also might be a property of the hPTH1R, we studied signal transduction via heterologously expressed hPTH1Rs in response to activation by hPTH(1-34), hPTH(1-31), and a C-truncated analog that does not increase rat bone mass in vivo, hPTH(1-30). In porcine LLC-PK1 cells that stably expressed recombinant hPTH1Rs, these three peptides activated AC identically (EC50 = 1-2 nM). In cells with comparable expression of rat PTH1Rs, AC activation by hPTH(1-34) and hPTH(1-31) again was identical, whereas full activation by hPTH(1-30) required higher concentrations (EC50 = 10 nM vs. 1 nM). Surprisingly, hPTH(1-31) fully stimulated phospholipase C (PLC), via both species of PTH1Rs, with potency that was similar (hPTH1Rs) or slightly reduced (rat PTH1Rs), relative to that of hPTH(1-34). hPTH(1-30), however, was 5-fold less potent than hPTH(1-34) in activating PLC via hPTH1Rs and showed weak and only partial activity via the rat PTH1R. Comparable results were obtained when human and rat PTH1Rs were transiently expressed heterologously in COS-7 cells or homologously in HEK 293 and UMR 106-01 cells, respectively. Binding affinities of these C-truncated peptides to human and rat PTH1Rs were concordant with their relative potencies in activating PLC. We conclude that hPTH(1-31) and, to a lesser extent, hPTH(1-30) can activate PLC, as well as AC, via both rat and human PTH1Rs. Accordingly, a role for PLC activation in the anabolic action of PTH in vivo cannot be excluded.

摘要

羧基（C）端截短的人（h）甲状旁腺激素（hPTH）类似物hPTH(1 - 31)，可在大鼠骨肉瘤细胞中激活腺苷酸环化酶（AC），但不激活蛋白激酶C，在体内对大鼠骨骼具有与hPTH(1 - 34)类似的合成代谢作用。因此，有人提出PTH(1 - 34)的这种作用完全是通过大鼠1型甲状旁腺激素/甲状旁腺激素相关肽（PTHrP）受体（PTH1R）刺激AC介导的。为了确定这种选择性信号转导模式是否也是hPTH1R的特性，我们研究了在异源表达的hPTH1R中，对hPTH(1 - 34)、hPTH(1 - 31)和一种在体内不会增加大鼠骨量的C端截短类似物hPTH(1 - 30)激活的信号转导情况。在稳定表达重组hPTH1R的猪LLC - PK1细胞中，这三种肽对AC的激活作用相同（半数有效浓度[EC50] = 1 - 2 nM）。在大鼠PTH1R表达相当的细胞中，hPTH(1 - 34)和hPTH(1 - 31)对AC的激活作用再次相同，而hPTH(1 - 30)完全激活AC需要更高的浓度（EC50 = 10 nM对1 nM）。令人惊讶的是，hPTH(1 - 31)通过两种PTH1R均可完全刺激磷脂酶C（PLC），相对于hPTH(1 - 34)，其效力相似（hPTH1R）或略有降低（大鼠PTH1R）。然而，hPTH(1 - 30)通过hPTH1R激活PLC的效力比hPTH(1 - 34)低5倍，并且通过大鼠PTH1R显示出较弱且仅部分的活性。当人及大鼠PTH1R分别在COS - 7细胞中异源瞬时表达或在HEK 293和UMR 106 - 01细胞中同源表达时，获得了类似的结果。这些C端截短肽与人及大鼠PTH1R的结合亲和力与其激活PLC的相对效力一致。我们得出结论，hPTH(1 - 31)以及在较小程度上hPTH(1 - 30)可通过大鼠和人PTH1R激活PLC以及AC。因此，不能排除PLC激活在PTH体内合成代谢作用中的作用。