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Original Article

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

Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea (J.H.L., A.F.W., K.M., C.W., M.A.S., S.Y.C., H.B.K., J.Y.S.); Department of Physiology, Ulsan University College of Medicine, Seoul, Republic of Korea (H.C.); Department of Aquaculture, Division of Aqua Life Science, Yeosu National University, Jeollanam-Do, Republic of Korea (W.-K.L.); and School of Biological Sciences, Seoul National University, Seoul, Republic of Korea (K.K.)

Abstract

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. Point-mutation studies indicate that four amino acids, Leu/Phe^7.38, Leu/Phe^7.43, Ala/Pro^7.46, and Pro/Cys^7.47 in TMH7 are critical for ligand selectivity as well as receptor conformation. Furthermore, a combinatory mutation (Pro^7.31-Pro^7.32-Ser^7.33 motif to Ser-Glu-Pro in EL3 and Leu^7.38, Leu^7.43, Ala^7.46, and Pro^7.47 to those of rat GnRHR) in gmGnRH-2 exhibited an approximately 500-fold increased sensitivity to GnRH-I, indicating that these residues are critical for discriminating GnRH-II from GnRH-I. [Trp⁷]GnRH-I and [Trp⁸]GnRH-I but not [His⁵]GnRH-I exhibit a higher potency in activating wild-type gmGnRHR-2 than native GnRH-I, indicating that amino acids at positions 7 and 8 of GnRHs are more important than position 5 for differential recognition by type I and type II GnRHRs. As a whole, these data suggest a molecular coevolution of ligands and their receptors and facilitate the understanding of the molecular interaction between GnRHs and their cognate receptors.

Address correspondence to: Dr. Jae Young Seong, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea. E-mail: jyseong{at}jnu.ac.kr

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