title: Constitutive activity in gonadotropin receptors.
abstract: Constitutively active mutants (CAMs) of gonadotropin receptors are, in general, rare conditions. Luteinizing hormone-choriogonadotropin receptor (LHCGR) CAMs provoke the dramatic phenotype of familial gonadotropin-independent isosexual male-limited precocious puberty, whereas in females, there is not yet any identified phenotype. Only one isolated follicle-stimulating hormone receptor (FSHR) CAM (Asp567Gly) has so far been detected in a single male patient, besides other FSHR weak CAMs linked to pregnancy-associated ovarian hyperstimulation syndrome or to impaired desensitization and internalization. Several animal models have been developed for studying enhanced gonadotropin action; in addition to unraveling valuable new information about the possible phenotypes of isolated FSHR and LHCGR CAMs in women, the information obtained from these mouse models has served multiple translational goals, including the development of new diagnostic and therapeutic targets as well as the prediction of phenotypes for mutations not yet identified in humans. Mutagenesis and computational studies have shed important information on the physiopathogenic mechanisms leading to constitutive activity of gonadotropin receptors; a common feature in these receptor CAMs is the release of stabilizing interhelical interactions between transmembrane domains (TMDs) 3 and 6 leading to an increase, with respect to the wild-type receptor, in the solvent accessibility at the cytosolic extension of TMDs 3, 5, and 6, which involves the highly conserved Glu/Asp-Arg-Tyr/Trp sequence. In this chapter, we summarize the structural features, functional consequences, and mechanisms that lead to constitutive activation of gonadotropin receptor CAMs and provide information on pharmacological approaches that might potentially modulate gonadotropin receptor CAM function.
authors.affiliation: Studium Consortium for Research and Training in Reproductive Sciences (sCORTS), Tours, France; Research Support Network, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" and Universidad Nacional Autónoma de México, México D.F., Mexico. Electronic address: aulloaa@unam.mx.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ulloa-Aguirre
authors.affiliation: Studium Consortium for Research and Training in Reproductive Sciences (sCORTS), Tours, France; BIOS Group, INRA, UMR85, Unité Physiologie de la Reproduction et des Comportements, Nouzilly, France; CNRS, UMR7247, Nouzilly, France; Université François Rabelais, Tours, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Reiter
authors.affiliation: Studium Consortium for Research and Training in Reproductive Sciences (sCORTS), Tours, France; Department of Biological Sciences, Wichita State University, Wichita, Kansas, USA.
authors.forename: George
authors.initials: G
authors.lastname: Bousfield
authors.affiliation: Studium Consortium for Research and Training in Reproductive Sciences (sCORTS), Tours, France; Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, New York, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Dias
authors.affiliation: Studium Consortium for Research and Training in Reproductive Sciences (sCORTS), Tours, France; Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
mesh_terms: D000818:Animals; D015195:Drug Design; D006801:Humans; D023421:Models, Animal; D009154:Mutation / Q000235:genetics; D011967:Receptors, Gonadotropin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011967:Receptors, Gonadotropin
keywords: Constitutively active mutants; Familial testotoxicosis; Follicle-stimulating hormone receptor; Gain-of-function mutations; Luteinizing hormone receptor; Ovarian hyperstimulation syndrome; Receptor activation