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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

Hormone Research Center (J.Y.S., L.W., D.Y.O., O.Y., K.M., J.H.L., J.M.S., H.S.C., H.B.K.), Chonnam National University, Kwangju, 500-757, Korea; School of Biological Sciences (K.K.), Seoul National University, Seoul 151-742, Korea; Laboratory of Cellular and Molecular Neuroendocrinology (H.V.), European Institute for Peptide Research, Institut National de la Santé et de la Recherche Médicale Unité 413, Unité Affiliée Centre National de la Recherche Scientifique, University of Rouen, 76821 Mont-Saint-Aignan Cedex, France

Address all correspondence and requests for reprints to: Hyuk Bang Kwon, Ph.D., Hormone Research Center, Chonnam National University, Kwangju 500-757, Korea. E-mail: kwonhb{at}chonnam.ac.kr.

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 G_s, whereas all bfGnRHRs and dyGnRHR-3 are coupled to both G_s and G_q/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.

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