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First published on January 5, 2005; DOI: 10.1124/mol.104.004887

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Received for publication July 13, 2004.
Revised December 28, 2004.
Accepted for publication January 4, 2005.

Extracellular Loop 3 (EL3) and EL3-Proximal Transmembrane Helix 7 of the Mammalian Type I and Type II GnRH Receptors Determine Differential Ligand Selectivity to GnRH-I and GnRH-II

Jian Hua Li 1, Han Choe 2, Ai Fen Wang 1, Kaushik Maiti 1, Chenbing Wang 1, Md Abdus Salam 1, Sang Young Chun 1, Won-Kyo Lee 3, Kyungjin Kim 4, Hyuk Bang Kwon 1, Jae Young Seong 1*

1 Chonnam National University 2 Ulsan University College of Medicine 3 Yoesu National University 4 Seoul Natioinal University

* Address correspondence to: E-mail: jyseong{at}jnu.ac.kr

Abstract

Mammalian type I and type II 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, the present 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/Phe7.43, Ala/Pro7.46, and Pro/Cys7.47 in TMH7 are critical for ligand selectivity as well as receptor conformation. Further, a combinatory mutation (Pro7.31-Pro7.32-Ser7.33 motif to Ser-Glu-Pro in EL3 and Leu7.38, Leu7.43, Ala7.46, 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 [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. Collectively, this study suggests a molecular coevolution of ligands and their receptors and facilitate the understanding of the molecular interaction between GnRHs and their cognate receptors.


Key words: Gonodotropins, Structure-activity relationships and modeling, Func. analysis receptor/ion channel mutants, Receptor binding studies


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