Liu Changlu, Chen Jingcai, Sutton Steven, Roland Barbara, Kuei Chester, Farmer Niven, Sillard Rannar, Lovenberg Timothy W
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., San Diego, California 92121, USA.
J Biol Chem. 2003 Dec 12;278(50):50765-70. doi: 10.1074/jbc.M308996200. Epub 2003 Sep 30.
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 35S-GTPgammaS incorporation in response to relaxin-3. However, whereas GPCR135 signaling could be converted to calcium mobilization using a Gqi5 or Galpha16 G-proteins, GPCR142 was only capable of functioning in the presence of Galpha16. In the accompanying article (Liu, C., Eriste, E., Sutton, S., Chen, J., Roland, B., Kuei, C., Farmer, N., Jörnvall, 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.
我们最近鉴定出胰岛素样肽松弛素-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种单一的孤儿受体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作出反应。令人惊讶的是，GPCR142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无反应。我们通过逆转录酶-PCR评估了GPCR142 mRNA在多种人体组织中的表达，发现在脑、肾、睾丸、胸腺、胎盘、前列腺、唾液腺、甲状腺和结肠中均有表达。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，但在大鼠中未能检测到任何完整的GPCR142转录本。关于细胞内信号传导，GPCR142与GPCR135相似，即它能有效抑制腺苷酸环化酶，并在松弛素-3的作用下刺激35S-GTPγS的掺入。然而，虽然使用Gqi5或Gα16 G蛋白可将GPCR135信号传导转化为钙动员，但GPCR142仅在Gα16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., Jörnvall, H., Sillard, R., and Lovenberg, T. W. (2003) J. Biol. Chem. 278, 50754-50764），我们提出这样的观点，即先前已证明与松弛素受体LGR7结合的松弛素-3很可能是GPCR135的内源性配体。在本报告中，我们展示了另一种受体GPCR142，它也被松弛素-3选择性激活。然而，GPCR142的解剖定位表明GPCR142可能具有不同的生理功能。
