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The Cloned Equine Thyrotropin Receptor Is Hypersensitive to Human Chorionic Gonadotropin; Identification of Three Residues in the Extracellular Domain Involved in Ligand Specificity

Institut National de la Santé et de la Recherche Médicale (J.R., A.L.-M., T.L., P.R., Y.M.), Unité 694, Equipe Avenir; Université d’Angers (Y.M., P.R.); Centre hospitalo universitaire d’Angers (Y.M., F.S.), Biochimie; and Centre hospitalo universitaire (P.R.), Centre de référence des maladies rares de la réceptivité hormonale, Endocrinologie, F-49000, Angers, France; and Universitat Autònoma de Barcelona (G.C., L.P.), Facultat de Medicina, Laboratori de Medicina Computacional, Unitat de Bioestadística, F-08193 Bellaterra, Spain

Address all correspondence and requests for reprints to: Patrice Rodien, M.D., Ph.D., Institut National de la Santé et de la Recherche Médicale Unité 694, Centre Hospitalier Universitaire d’Angers, 4 rue Larrey, 49933 Angers cedex 09, France. E-mail: PaRodien{at}chu-angers.fr.

The receptors for TSH, LH/chorionic gonadotropin (CG), and FSH belong to the same subfamily of G protein-coupled receptors. The specificity of recognition of their cognate hormone involves a limited number of residues in the leucine-rich repeats present in the N-terminal ectodomain of the receptor. It is admitted that receptors of this subfamily coevoluted with their respective ligands. The secretion of CG is restricted to gestation of primates and Equidae. We hypothesized that, facing the challenge of a new hormone, the glycoprotein hormone receptors would have evolved differently in Equidae and human so that distinct residues are involved in hormone specificity. In particular, it is known that equine CG has a dual (FSH and LH) activity when administered to other species. In the present work, we cloned and characterized functionally the equine TSH receptor (TSHR), which shares 89% homology with the human TSHR. The equine TSHR is not responsive to equine CG but is more sensitive to human CG than the human TSHR. Three residues, at positions 60, 229, and 235 of the ectodomain, are responsible for this difference in sensitivity as shown by modelization and targeted mutagenesis, followed by in vitro functional characterization. The phylogenetic approach is a suitable approach to identify determinants of specificity of receptors.