Gonadotropin-releasing hormone (GnRH) regulates the reproductive system through the cognate GnRH receptor (GnRHR) in vertebrates. In this study, we cloned a cDNA encoding the full-length open reading frame sequence for green monkey type-II GnRHR (gmGnRHR-2) from the genomic DNA of CV-1 cells. Transient transfection study showed that gmGnRHR-2 was able to induce both c-fos promoter- and cAMP responsive element-driven transcriptional activities, indicating that gmGnRHR-2 couples to both Gs- and Gq/11-linked signaling pathways. gmGnRHR-2 responded better to GnRH-2 ([His5, Trp7, Tyr8]GnRH) than GnRH-1 ([Tyr5, Leu7, Arg8]GnRH). Substitutions of His5, Trp7, and/or Tyr8 in GnRH-1 increased the potency to activate gmGnRHR-2, suggesting that individual His5, Trp7, and Tyr8 in GnRH-2 contributed to differential ligand sensitivity of gmGnRHR-2. Substitution of D-Ala for Gly6 in GnRH-2 increased the potency to activate the receptor, suggesting that GnRH-2 has a constrained conformation when it binds to the receptor. GnRH-induced gmGnRHR-2 activation was specifically inhibited by GnRH-2 antagonists, Trptorelix-1 and -2, but not by a GnRH-1 antagonist, Cetrorelix. In conclusion, gmGnRHR-2 revealed preferential ligand selectivity for GnRH-2 and its analogs, suggesting that gmGnRHR-2 has a functional activity that is different from mammalian type-I GnRHRs but similar to non-mammalian GnRHRs.
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Extracellular loop 3 (EL3) and EL3-proximal transmembrane helix 7 of the mammalian type I and type II gonadotropin-releasing hormone (GnRH) receptors determine differential ligand selectivity to GnRH-I and GnRH-II.
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Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
Mammalian type I and II gonadotropin-releasing hormone (GnRH) receptors (GnRHRs) show differential ligand preference for GnRH-I and GnRH-II, respectively. Using a variety of chimeric receptors based on green monkey GnRHR-2 (gmGnRHR-2), a representative type II GnRHR, and rat GnRHR, a representative type I GnRHR, this study elucidated specific domains responsible for this ligand selectivity. A chimeric gmGnRHR-2 with the extracellular loop 3 (EL3) and EL3-proximal transmembrane helix 7 (TMH7) of rat GnRHR showed a great increase in ligand sensitivity to GnRH-I but not to GnRH-II.
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Hormone Research Center and Department of Biology, Chonnam National University, Gwangju 500-757, Korea.
Recently, we identified three types of non-mammalian gonadotropin-releasing hormone receptors (GnRHR) in the bullfrog (designated bfGnRHR-1-3), and a mammalian type-II GnRHR in green monkey cell lines (denoted gmGnRHR-2). All these receptors responded better to GnRH-II than GnRH-I, while mammalian type-I GnRHR showed greater sensitivity to GnRH-I than GnRH-II. In the present study, we designed new GnRH-II analogs and examined whether they activated or inhibited non-mammalian and mammalian type-II GnRHRs.
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Hormone Research Center, Chonnam National University, Gwangju 500-757, South Korea.
Gonadotropin-releasing hormone (GnRH) regulates the reproductive system through the cognate GnRH receptor (GnRHR) in vertebrates. In this study, we cloned a cDNA encoding the full-length open reading frame sequence for green monkey type-II GnRHR (gmGnRHR-2) from the genomic DNA of CV-1 cells. Transient transfection study showed that gmGnRHR-2 was able to induce both c-fos promoter- and cAMP responsive element-driven transcriptional activities, indicating that gmGnRHR-2 couples to both Gs- and Gq/11-linked signaling pathways.
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