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

Jian Hua Li, Han Choe, Ai Fen Wang, Kaushik Maiti, Chengbing Wang, Abdus Salam, Sang Young Chun, Won Kyo Lee, Kyungjin Kim, Hyuk Bang Kwon, Jae Young Seong

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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/Phe7.38, Leu/Phe 7.43, Ala/Pro7.46, and Pro/Cys7.47 in TMH7 are critical for ligand selectivity as well as receptor conformation. Furthermore, a combinatory mutation (Pro7.31-Pro7.32-Ser7.33 motif to Ser-Glu-Pro in EL3 and Leu7.38, Leu7.43, Ala 7.46, and Pro7.47 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 [HiS 5]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.

Original languageEnglish
Pages (from-to)1099-1110
Number of pages12
JournalMolecular Pharmacology
Issue number4
Publication statusPublished - 2005 Apr 1
Externally publishedYes


ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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