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Submitted on April 3, 2006
Accepted on September 5, 2006
Medical Research Council / University of Cape Town Research Group for Receptor Biology, Institute for Infectious Diseases and Molecular Medicine and Division of Medical Biochemistry (S.M., R.P.M., A.A.K., C.A.F.), University of Cape Town Faculty of Health Sciences, and Department of Medicine, Groote Schuur Hospital (C.A.F.), Observatory 7925, Cape Town, South Africa; Medical Research Council Human Reproductive Sciences Unit (Z.L., R.P.M.), The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH 16 4TJ, Scotland, United Kingdom, and Indiana University School of Medicine (R.W.R.), Indianapolis, Indiana 46202
* To whom correspondence should be addressed. E-mail: flanagan{at}curie.uct.ac.za.
GnRH I regulates reproduction. A second form, designated GnRH II, selectively binds type II GnRH receptors. Amino acids of the type I GnRH receptor required for binding of GnRH I (Asp2.61(98), Asn2.65(102) and Lys3.32(121)) are conserved in the type II GnRH receptor, but their roles in receptor function are unknown. We have delineated their functions using mutagenesis, signaling and binding assays, immunoblotting and computational modeling.
Mutating Asp2.61(97) to Glu or Ala, Asn2.65(101) to Ala, or Lys3.32(120) to Gln decreased potency of GnRH II-stimulated inositol phosphate production. Consistent with proposed roles in ligand recognition, mutations eliminated measurable binding of GnRH II, while expression of mutant receptors was not decreased.
In detailed analysis of how these residues affect ligand-dependent signaling, [Trp2]-GnRH I showed lesser decreases in potency than GnRH I at the Asp2.61(97)Glu mutant. In contrast, [Trp2]-GnRH II showed the same loss of potency as GnRH II at this mutant. This suggests that Asp2.61(97) contributes to recognition of His2 of GnRH I, but not of GnRH II. GnRH II showed a large decrease in potency at the Asn2.65(101)Ala mutant compared with analogs lacking the C=O group of Gly10NH2. This suggests that Asn2.65(101) recognizes Gly10NH2 of GnRH II. GnRH agonists showed large decreases in potency at the Lys3.32(120)Gln mutant, but antagonist activity was unaffected. This suggests that Lys3.32(120) recognizes agonists, but not antagonists, as in the type I receptor. These data indicate that roles of conserved residues are similar, but not identical in the type I and II GnRH receptors.
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