Ala/Thr201 in extracellular loop 2 and Leu/Phe290 in transmembrane domain 6 of type 1 frog gonadotropin-releasing hormone receptor confer differential ligand sensitivity and signal transduction

Jae Young Seong, Li Wang, Dayoung Oh, Oim Yun, Kaushik Maiti, Jian Hua Li, Jae Mok Soh, Hueng Sik Choi, Kyungjin Kim, Hubert Vaudry, Hyuk Bang Kwon

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Recently, we have identified three distinct types of bullfrog GnRH receptor (designated bfGnRHR-1, bfGnRHR-2, and bfGnRHR-3). In the present study, we have isolated three GnRHR clones in Rana dybowskii (dyGnRHR-1, dyGnRHR-2, and dyGnRHR-3). Despite high homology of dyGnRHRs with the corresponding bfGnRHRs, dyGnRHRs revealed different signaling pathways and ligand sensitivity compared with the bfGnRHR counterparts. Activation of dyGnRHRs with GnRH stimulated cAMP-mediated gene expression. However, dyGnRHR-3 but not dyGnRHR-1 and -2 induced c-fos promoter-driven gene expression. Consistently, dyGnRHR-1 and dyGnRHR-2 were not able to increase GnRH-induced inositol phosphate accumulation, whereas all bfGnRHRs and dyGnRHR-3 were, indicating that dyGnRHR-1 and dyGnRHR-2 are coupled to solely Gs, whereas all bfGnRHRs and dyGnRHR-3 are coupled to both Gs and Gq/11. Moreover, dyGnRHR-1 and dyGnRHR-2 showed about 10-fold less sensitivity to each ligand than that of the bfGnRHR counterparts. Using type 1 chimeric and point-mutated receptors, we further elucidated that specific amino acids, Ala/Thr201 in extracellular loop 2 and Leu/Phe290 in transmembrane domain 6 of the type 1 receptor, are responsible for ligand sensitivity and signal transduction pathway. Particularly, substitution of Leu290 to Phe in dyGnRHR-1 increased GnRH-induced inositol phosphate production as well as c-fos promoter-driven gene expression whereas substitution of Phe290 to Leu in bfGnRHR-1 decreased those activities. Collectively, these results demonstrate the presence of three types of GnRHR in amphibians, and suggest species- and type-specific ligand recognition and different signaling pathways in frog GnRHRs.

Original languageEnglish (US)
Pages (from-to)454-466
Number of pages13
JournalEndocrinology
Volume144
Issue number2
DOIs
StatePublished - Feb 1 2003

ASJC Scopus subject areas

  • Endocrinology

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