Involvement of amino acids flanking Glu7.32 of the Gonadotropin-releasing hormone receptor in the selectivity of antagonists

Chengbing Wang, Da Young Oh, Kaushik Maiti, Hyuk Bang Kwon, Jun Cheon, Jong-Ik Hwang, Jae Young Seong

Research output: Contribution to journalArticle

Abstract

The Glu/Asp7.32 residue in extracellular loop 3 of the mammalian type-I gonadotropin-releasing hormone receptor (GnRHR) interacts with Arg8 of GnRH-I, conferring preferential ligand selectivity for GnRH-I over GnRH-II. Previously, we demonstrated that the residues (Ser and Pro) flanking Glu/Asp7.32 also play a role in the differential agonist selectivity of mammalian and non-mammalian GnRHRs. In this study, we examined the differential antagonist selectivity of wild type and mutant GnRHRs in which the Ser and Pro residues were changed. Cetrorelix, a GnRH-I antagonist, and Trptorelix-2, a GnRH-II antagonist, exhibited high selectivity for mammalian type-I and non-mammalian GnRHRs, respectively. The inhibitory activities of the antagonists were dependent on agonist concentration and subtype. Rat GnRHR in which the Ser-Glu-Pro (SEP) motif was changed to Pro-Glu-Val (PEV) or Pro-Glu-Ser (PES) had increased sensitivity to Trptorelix-2 but decreased sensitivity to Cetrorelix. Mutant bullfrog GnRHR-1 with the SEP motif had the reverse antagonist selectivity, with redueed sensitivity to Trptorelix-2 but increased sensitivity to Cetrorelix. These findings indicate that the residues flanking Glu7.32 are important for antagonist as well as agonist selectivity.

Original languageEnglish
Pages (from-to)91-98
Number of pages8
JournalMolecules and Cells
Volume25
Issue number1
Publication statusPublished - 2008 Feb 29

Fingerprint

LHRH Receptors
Gonadotropin-Releasing Hormone
Amino Acids
Rana catesbeiana
Ligands
acetyl-(2-naphthyl)alanyl-4-chlorophenylalanyl-3-(3-pyridinyl)alanyl-seryl-histidyl-n5-aminocarbonylornithyl-tryptophyl-tyrosyl-prolyl-alaninamide
cetrorelix
His(5)-Trp(7)-Tyr(8)-lHRH

Keywords

  • Antagonist selectivity
  • Extracellular loop 3 (ECL3)
  • G protein-coupled receptor (GPCR)
  • GnRH receptor
  • Gonad-otropin-releasing hormone (GnRH)
  • Ser-Glu-Pro (SEP) motif

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Involvement of amino acids flanking Glu7.32 of the Gonadotropin-releasing hormone receptor in the selectivity of antagonists. / Wang, Chengbing; Oh, Da Young; Maiti, Kaushik; Kwon, Hyuk Bang; Cheon, Jun; Hwang, Jong-Ik; Seong, Jae Young.

In: Molecules and Cells, Vol. 25, No. 1, 29.02.2008, p. 91-98.

Research output: Contribution to journalArticle

@article{f4c6cfe659734706b22a8b5ac97acbf1,
title = "Involvement of amino acids flanking Glu7.32 of the Gonadotropin-releasing hormone receptor in the selectivity of antagonists",
abstract = "The Glu/Asp7.32 residue in extracellular loop 3 of the mammalian type-I gonadotropin-releasing hormone receptor (GnRHR) interacts with Arg8 of GnRH-I, conferring preferential ligand selectivity for GnRH-I over GnRH-II. Previously, we demonstrated that the residues (Ser and Pro) flanking Glu/Asp7.32 also play a role in the differential agonist selectivity of mammalian and non-mammalian GnRHRs. In this study, we examined the differential antagonist selectivity of wild type and mutant GnRHRs in which the Ser and Pro residues were changed. Cetrorelix, a GnRH-I antagonist, and Trptorelix-2, a GnRH-II antagonist, exhibited high selectivity for mammalian type-I and non-mammalian GnRHRs, respectively. The inhibitory activities of the antagonists were dependent on agonist concentration and subtype. Rat GnRHR in which the Ser-Glu-Pro (SEP) motif was changed to Pro-Glu-Val (PEV) or Pro-Glu-Ser (PES) had increased sensitivity to Trptorelix-2 but decreased sensitivity to Cetrorelix. Mutant bullfrog GnRHR-1 with the SEP motif had the reverse antagonist selectivity, with redueed sensitivity to Trptorelix-2 but increased sensitivity to Cetrorelix. These findings indicate that the residues flanking Glu7.32 are important for antagonist as well as agonist selectivity.",
keywords = "Antagonist selectivity, Extracellular loop 3 (ECL3), G protein-coupled receptor (GPCR), GnRH receptor, Gonad-otropin-releasing hormone (GnRH), Ser-Glu-Pro (SEP) motif",
author = "Chengbing Wang and Oh, {Da Young} and Kaushik Maiti and Kwon, {Hyuk Bang} and Jun Cheon and Jong-Ik Hwang and Seong, {Jae Young}",
year = "2008",
month = "2",
day = "29",
language = "English",
volume = "25",
pages = "91--98",
journal = "Molecules and Cells",
issn = "1016-8478",
publisher = "Korean Society for Molecular and Cellular Biology",
number = "1",

}

TY - JOUR

T1 - Involvement of amino acids flanking Glu7.32 of the Gonadotropin-releasing hormone receptor in the selectivity of antagonists

AU - Wang, Chengbing

AU - Oh, Da Young

AU - Maiti, Kaushik

AU - Kwon, Hyuk Bang

AU - Cheon, Jun

AU - Hwang, Jong-Ik

AU - Seong, Jae Young

PY - 2008/2/29

Y1 - 2008/2/29

N2 - The Glu/Asp7.32 residue in extracellular loop 3 of the mammalian type-I gonadotropin-releasing hormone receptor (GnRHR) interacts with Arg8 of GnRH-I, conferring preferential ligand selectivity for GnRH-I over GnRH-II. Previously, we demonstrated that the residues (Ser and Pro) flanking Glu/Asp7.32 also play a role in the differential agonist selectivity of mammalian and non-mammalian GnRHRs. In this study, we examined the differential antagonist selectivity of wild type and mutant GnRHRs in which the Ser and Pro residues were changed. Cetrorelix, a GnRH-I antagonist, and Trptorelix-2, a GnRH-II antagonist, exhibited high selectivity for mammalian type-I and non-mammalian GnRHRs, respectively. The inhibitory activities of the antagonists were dependent on agonist concentration and subtype. Rat GnRHR in which the Ser-Glu-Pro (SEP) motif was changed to Pro-Glu-Val (PEV) or Pro-Glu-Ser (PES) had increased sensitivity to Trptorelix-2 but decreased sensitivity to Cetrorelix. Mutant bullfrog GnRHR-1 with the SEP motif had the reverse antagonist selectivity, with redueed sensitivity to Trptorelix-2 but increased sensitivity to Cetrorelix. These findings indicate that the residues flanking Glu7.32 are important for antagonist as well as agonist selectivity.

AB - The Glu/Asp7.32 residue in extracellular loop 3 of the mammalian type-I gonadotropin-releasing hormone receptor (GnRHR) interacts with Arg8 of GnRH-I, conferring preferential ligand selectivity for GnRH-I over GnRH-II. Previously, we demonstrated that the residues (Ser and Pro) flanking Glu/Asp7.32 also play a role in the differential agonist selectivity of mammalian and non-mammalian GnRHRs. In this study, we examined the differential antagonist selectivity of wild type and mutant GnRHRs in which the Ser and Pro residues were changed. Cetrorelix, a GnRH-I antagonist, and Trptorelix-2, a GnRH-II antagonist, exhibited high selectivity for mammalian type-I and non-mammalian GnRHRs, respectively. The inhibitory activities of the antagonists were dependent on agonist concentration and subtype. Rat GnRHR in which the Ser-Glu-Pro (SEP) motif was changed to Pro-Glu-Val (PEV) or Pro-Glu-Ser (PES) had increased sensitivity to Trptorelix-2 but decreased sensitivity to Cetrorelix. Mutant bullfrog GnRHR-1 with the SEP motif had the reverse antagonist selectivity, with redueed sensitivity to Trptorelix-2 but increased sensitivity to Cetrorelix. These findings indicate that the residues flanking Glu7.32 are important for antagonist as well as agonist selectivity.

KW - Antagonist selectivity

KW - Extracellular loop 3 (ECL3)

KW - G protein-coupled receptor (GPCR)

KW - GnRH receptor

KW - Gonad-otropin-releasing hormone (GnRH)

KW - Ser-Glu-Pro (SEP) motif

UR - http://www.scopus.com/inward/record.url?scp=42949169428&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=42949169428&partnerID=8YFLogxK

M3 - Article

VL - 25

SP - 91

EP - 98

JO - Molecules and Cells

JF - Molecules and Cells

SN - 1016-8478

IS - 1

ER -