Identification of MrgX2 as a human G-protein-coupled receptor for proadrenomedullin N-terminal peptides
Identification of MrgX2 as a human G-protein-coupled receptor for proadrenomedullin N-terminal peptides
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DOI：
10.1016/j.bbrc.2005.03.088
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发表时间：
2005-05-20
影响因子：
3.1
通讯作者：
Katou, M
中科院分区：
文献类型：
--
作者：
Kamohara, M;Matsuo, A;Katou, M
肾上腺髓质素前体N-末端20肽(PAMP[1-20]/PAMP-20)及其截短类似物PAMP[9-20]/PAMP-12是通过抑制交感神经末梢和肾上腺嗜铬细胞分泌儿茶酚胺而引起降压的内源性多肽。虽然PAMP的结合部位分布广泛。其受体的性质一直难以捉摸。为了鉴定潜在的PAMP受体(S)，我们发现人G蛋白偶联受体MRGX2被PAMP特异性激活。虽然先前的一项研究表明，MRGX2是皮质素的受体，皮质素是一种参与睡眠调节和运动活动的神经肽，但我们目前的数据表明，对MRgX2的兴奋作用的等级顺序是：PAMP-12>；皮质抑素>；PAMP-20。这些活性通过抑制Forsklin升高的cAMP积累、钙动员和[S-35]鸟苷5‘-(γ-硫代)三磷酸结合试验得到证实。这些发现表明，MRgX2不仅与G(阿尔法Q)，而且还与G(阿尔法I)配对，这与先前关于PAMP信号的药理学特征的报道一致。此外，通过免疫组织化学染色，我们发现在肾上腺嗜铬细胞和背根神经节中均有表达。根据这些结果，我们得出结论，MRGX2是一种潜在的人类PAMP-12受体，它调节肾上腺儿茶酚胺的分泌。这一发现最终将有助于更好地理解肾上腺髓质素原多肽的病理生理学作用。(C)2005 Elsevier Inc.保留所有权利。
Proadrenomedullin N-terminal 20 peptide (PAMP[1-20]/PAMP-20) and its truncated analog, PAMP[9-20]/PAMP-12, are endogenous peptides that elicit hypotension through inhibiting catecholamine secretion from sympathetic nerve endings and adrenal chromaffin cells. Although the binding sites for PAMP are widely distributed.. the nature of its receptor has been elusive. In an effort to identify potential PAMP receptor(s), we found that a human G-protein-coupled receptor, MrgX2, was specifically activated by PAMP. Although a previous study revealed that MrgX2 was a receptor for cortistatin, a neuropeptide involved in sleep regulation and locomotor activity, our present data indicated that the rank order of the agonistic effect against MrgX2 was "PAMP-12 > cortistatin > PAMP-20". These activities were confirmed by the inhibition of the forskolin-elevated cAMP accumulation, Ca2+ mobilization, and [S-35]guanosine 5'-(gamma-thio)triphosphate binding assays. These findings suggest that MrgX2 couples with not only G(alpha q) but also G(alpha i), consistent with previous reports on the pharmacological profile of PAMP signaling. Furthermore, by immunostaining, we found that MrgX2 was expressed in the adrenal chromaffin cells as well as the dorsal root ganglia. From these results, we concluded that MrgX2 is a potential human PAMP-12 receptor that regulates catecholamine secretion from adrenal glands. The present discovery will eventually lead to a better understanding of the pathophysiological role of proadrenomedullin peptides. (c) 2005 Elsevier Inc. All rights reserved.