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J. Biol. Chem., Vol. 276, Issue 11, 7754-7761, March 16, 2001
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From the Mammalian receptors for gonadotropin-releasing
hormone (GnRH) have over 85% sequence homology and similar ligand
selectivity. Biological studies indicated that the chicken GnRH
receptor has a distinct pharmacology, and certain antagonists of
mammalian GnRH receptors function as agonists. To explore the
structural determinants of this, we have cloned a chicken pituitary
GnRH receptor and demonstrated that it has marked differences in
primary amino acid sequence (59% homology) and in its interactions
with GnRH analogs. The chicken GnRH receptor had high affinity for mammalian GnRH (Ki 4.1 ± 1.2 nM)
, similar to the human receptor (Ki 4.8 ± 1.2 nM). But, in contrast to the human receptor, it also had
high affinity for chicken GnRH ([Gln8]GnRH) and GnRH II
([His5,Trp7,Tyr8]GnRH)
(Ki 5.3 ± 0.5 and 0.6 ± 0.01 nM). Three mammalian receptor antagonists were also pure
antagonists in the chicken GnRH receptor. Another three, characterized
by D-Lys6 or
D-isopropyl-Lys6 moieties, functioned as pure
antagonists in the human receptor but were full or partial agonists in
the chicken receptor. This suggests that the Lys side chain interacts
with functional groups of the chicken GnRH receptor to stabilize it in
the active conformation and that these groups are not available in the
activated human GnRH receptor. Substitution of the human receptor
extracellular loop two with the chicken extracellular loop two
identified this domain as capable of conferring agonist activity to
mammalian antagonists. Although functioning of antagonists as agonists
has been shown to be species-dependent for several GPCRs, the
dependence of this on an extracellular domain has not been described.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AJ304414.
A Chicken Gonadotropin-releasing Hormone Receptor That Confers
Agonist Activity to Mammalian Antagonists
IDENTIFICATION OF D-LYS6 IN THE LIGAND
AND EXTRACELLULAR LOOP TWO OF THE RECEPTOR AS DETERMINANTS*
§,¶,
,**,,,
MRC/UCT Research Unit for Molecular
Reproductive Endocrinology and the ¶ Department of Medicine,
University of Cape Town, Observatory 7925, South Africa, ** MRC Human
Reproductive Sciences Unit, 37 Chalmers Street,
Edinburgh EH3 9ET, Scotland, United Kingdom,
§§ Division of Integrative Biology, Roslin
Institute (Edinburgh), Roslin, Midlothian EH25 9PS, United Kingdom,
and the ¶¶ Fishberg Research Center in Neurobiology, the
Mount Sinai Medical Center, New York, New York 10029
*
This work was supported by the Medical Research Council and
National Research Foundation (South Africa), the University of Cape
Town, the British Council, the Medical Research Council (UK), the
Biotechnology and Biological Sciences Research Council
(Competitive Strategic Grant), and National Institutes of Health Grant
RO1.DK46943.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Current address: Dept. of Biochemistry, University of Cape
Town, Rondebosch 7700, South Africa.
Current address: Dept. of Biochemistry, University of
Stellenbosch, Matieland 7602, South Africa.
To whom correspondence should be addressed: MRC Human
Reproductive Sciences Unit, 37 Chalmers Street, Edinburgh EH3 9ET,
Scotland, UK. Tel.: 131 229 2575; Fax: 131 228 5571.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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