Identification of relaxin-3/INSL7 as a ligand for GPCR142
Identification of relaxin-3/INSL7 as a ligand for GPCR142
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DOI：
10.1074/jbc.m308996200
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发表时间：
2003-12-12
影响因子：
4.8
通讯作者：
Lovenberg, TW
中科院分区：
文献类型：
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作者：
Liu, CL;Chen, JC;Lovenberg, TW
我们最近发现胰岛素样肽松弛素-3(又名INSL7)是一种孤儿G蛋白偶联受体GPCR135(又名生长抑素和血管紧张素样肽受体)的内源性配体。对与GPCR135相关的可能受体的分析揭示了一个单一的孤儿受体GPCR142。因此，我们测试了GPCR142是否也能对松弛素-3或相关的胰岛素样分子产生反应。令人惊讶的是，GPCR142可以被纳摩尔浓度的松弛素-3激活，但对所有其他已知的胰岛素样肽完全没有反应。我们用逆转录-聚合酶链式反应检测了GPCR142在人类不同组织中的表达，发现GPCR142在脑、肾、睾丸、胸腺、胎盘、前列腺癌、唾液腺、甲状腺和结肠中都有表达。在对其他物种的分析中，我们能够找到GPCR142的全长小鼠同源物，但无法在大鼠身上检测到任何完整的GPCR142转录本。在细胞内信号转导方面，GPCR142类似于GPCR135，它有效地抑制腺苷环化酶，并刺激松弛蛋白-3对S-35-GTP-GammaS的掺入。然而，GPCR135信号可以通过G(Q5)或Galpha(16)G蛋白被转化为钙动员，而GPCR142只有在Galpha(16)存在的情况下才能发挥作用。在随附的文章中(Liu，C.，Eriste，E.，Sutton，S.，Chen，J.，Roland，B.，Kuei，C.，Farmer，N.，Jornvall，H.，Sillard，R.，and Lovenberg，T.W.(2003)J.Biol.化学。278,50754-50764)，我们提出了这样的情况，即先前已被证明与松弛素受体LGR7结合的松弛蛋白-3最有可能是GPCR135的内源配体。在这份报告中，我们展示了一个额外的受体，GPCR142，它也被松弛蛋白-3选择性地激活。然而，GPCR142的解剖定位表明，GPCR142可能具有不同的生理功能。
We have recently identified the insulin-like peptide relaxin-3 (aka INSL7) as the endogenous ligand for an orphan G-protein-coupled receptor, GPCR135 (aka somatostatin- and angiotensin-like peptide receptor). Analysis of possible receptors related to GPCR135 revealed a single orphan receptor, GPCR142. Thus, we tested whether GPCR142 could also respond to relaxin-3 or related insulin-like molecules. Surprisingly, GPCR142 was activated by nanomolar concentrations of relaxin-3 but was completely unresponsive to all other known insulin-like peptides. We evaluated by reverse transcriptase-PCR the expression of GPCR142 mRNA in a variety of human tissues and found expression in brain, kidney, testis, thymus, placenta, prostate, salivary gland, thyroid, and colon. In an analysis of other species, we were able to find a full-length mouse homolog of GPCR142, but were unable to detect any complete GPCR142 transcripts in rat. With respect to intracellular signaling, GPCR142 is similar to GPCR135 in that it potently inhibits adenylate cyclase and stimulates S-35-GTPgammaS incorporation in response to relaxin-3. However, whereas GPCR135 signaling could be converted to calcium mobilization using a G(qi5) or Galpha(16) G-proteins, GPCR142 was only capable of functioning in the presence of Galpha(16). In the accompanying article (Liu, C., Eriste, E., Sutton, S., Chen, J., Roland, B., Kuei, C., Farmer, N., Jornvall, H., Sillard, R., and Lovenberg, T. W. (2003) J. Biol. Chem. 278, 50754-50764), we present the case that relaxin-3, which has previously been shown to bind to the relaxin receptor LGR7, is most likely the endogenous ligand for GPCR135. In this report, we show an additional receptor, GPCR142, which is also selectively activated by relaxin-3. However, the anatomical localization of GPCR142 suggests that GPCR142 may have different physiological functions.