title: GnRH-II analogs for selective activation and inhibition of non-mammalian and type-II mammalian GnRH receptors.
abstract: 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. [D-Ala6]GnRH-II, with D-Ala substituted for Gly6 in GnRH-II, increased inositol phosphate (IP) production in cells stably expressing non-mammalian GnRHRs more effectively than native GnRH-II. However, it exhibited lower activity for mammalian type-I GnRHR than GnRH-I itself. Trptorelix-1, a GnRH-II antagonist, inhibited GnRH-induced IP production in cells expressing non-mammalian GnRHRs more effectively than Cetrorelix, a GnRH-I antagonist. Trptorelix-1, however, had lower potency for mammalian type-I GnRHR than Cetrorelix. Ligand-receptor binding assays revealed that [D-Ala6]GnRH-II and Trptorelix-1 have higher affinities for non-mammalian GnRHRs but lower affinities for mammalian type-I GnRHR than GnRH-II and Cetrorelix, respectively. Moreover, [D-Ala6]GnRH-II and Trptorelix-1 had a higher affinity for gmGnRHR-2 than GnRH-II and Cetrorelix, respectively. These results indicate that [D-Ala6]GnRH-II and Trptorelix-1 are highly effective agonist and antagonist, respectively, for non-mammalian and type-II mammalian GnRHRs.
authors.affiliation: Hormone Research Center and Department of Biology, Chonnam National University, Gwangju 500-757, Korea.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Maiti
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Li
authors.forename: Ai Fen
authors.initials: AF
authors.lastname: Wang
authors.forename: Sujata
authors.initials: S
authors.lastname: Acharjee
authors.forename: Wang Phil
authors.initials: WP
authors.lastname: Kim
authors.forename: Wook-Bin
authors.initials: WB
authors.lastname: Im
authors.forename: Hyuk Bang
authors.initials: HB
authors.lastname: Kwon
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Seong
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000096:biosynthesis; D008024:Ligands; D011485:Protein Binding; D011892:Rana catesbeiana; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C484844:GNRHR protein, human; C427484:GNRHR2 protein, human; D006727:Hormone Antagonists; D007295:Inositol Phosphates; D008024:Ligands; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; C062876:cetrorelix