Genomes and Genes
Summary: Receptors with a 6-kDa protein on the surfaces of cells that secrete LUTEINIZING HORMONE or FOLLICLE STIMULATING HORMONE, usually in the adenohypophysis. LUTEINIZING HORMONE-RELEASING HORMONE binds to these receptors, is endocytosed with the receptor and, in the cell, triggers the release of LUTEINIZING HORMONE or FOLLICLE STIMULATING HORMONE by the cell. These receptors are also found in rat gonads. INHIBINS prevent the binding of GnRH to its receptors.
- Shimizu M, Bedecarrats G. Identification of a novel pituitary-specific chicken gonadotropin-releasing hormone receptor and its splice variants. Biol Reprod. 2006;75:800-8 pubmed..In conclusion, we isolated a novel GNRHR and its splice variants in chickens, and spatial and temporal gene expression patterns suggest that this receptor plays an important role in the regulation of reproduction. ..
- Sedgley K, Finch A, Caunt C, McArdle C. Intracellular gonadotropin-releasing hormone receptors in breast cancer and gonadotrope lineage cells. J Endocrinol. 2006;191:625-36 pubmed..Manipulations favoring such trafficking may facilitate selective targeting of extra-pituitary GnRHRs. ..
- Maudsley S, Davidson L, Pawson A, Chan R, Lopez de Maturana R, Millar R. Gonadotropin-releasing hormone (GnRH) antagonists promote proapoptotic signaling in peripheral reproductive tumor cells by activating a Galphai-coupling state of the type I GnRH receptor. Cancer Res. 2004;64:7533-44 pubmed..Therefore the ability of GnRH receptor antagonists to exert an antiproliferative effect on reproductive tumors may be dependent on ligand-selective activation of the Galpha(i)-coupled form of the type I GnRH receptor. ..
- Janovick J, Knollman P, Brothers S, Ayala Yáñez R, Aziz A, Conn P. Regulation of G protein-coupled receptor trafficking by inefficient plasma membrane expression: molecular basis of an evolved strategy. J Biol Chem. 2006;281:8417-25 pubmed
- Bhagavath B, Podolsky R, Ozata M, Bolu E, Bick D, Kulharya A, et al. Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism. Fertil Steril. 2006;85:706-13 pubmed..Further study of genes that regulate hypothalamic-pituitary development and function will likely reveal important information regarding the development of normal puberty in humans. ..
- Oosterom J, van Doornmalen E, Lobregt S, Blomenröhr M, Zaman G. High-throughput screening using beta-lactamase reporter-gene technology for identification of low-molecular-weight antagonists of the human gonadotropin releasing hormone receptor. Assay Drug Dev Technol. 2005;3:143-54 pubmed..Based on technology comparison, it is not adequate to assume that the same hits would be found regardless of which assay technology is used. ..
- Knollman P, Janovick J, Brothers S, Conn P. Parallel regulation of membrane trafficking and dominant-negative effects by misrouted gonadotropin-releasing hormone receptor mutants. J Biol Chem. 2005;280:24506-14 pubmed..These studies establish the relation between the DN effect and altered receptor trafficking and explain why hGnRHR is more susceptible to defective trafficking by disease-related point mutations than rodent counterparts. ..
- Naor Z. Signaling by G-protein-coupled receptor (GPCR): studies on the GnRH receptor. Front Neuroendocrinol. 2009;30:10-29 pubmed publisher..The connectivity maps will open a new vista for exploring the direct effects of GnRH analogs in tumors and the design of novel combined therapies for fertility control, reproductive disorders and cancers. ..
- Conn P, Ulloa Aguirre A, Ito J, Janovick J. G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo. Pharmacol Rev. 2007;59:225-50 pubmed
- Janovick J, Brothers S, Cornea A, Bush E, Goulet M, Ashton W, et al. Refolding of misfolded mutant GPCR: post-translational pharmacoperone action in vitro. Mol Cell Endocrinol. 2007;272:77-85 pubmed
- Wilson A, Salamat M, Haasl R, Roche K, Karande A, Meethal S, et al. Human neurons express type I GnRH receptor and respond to GnRH I by increasing luteinizing hormone expression. J Endocrinol. 2006;191:651-63 pubmed..Post-reproductive surges in GnRH I secretion may explain the accumulation of LH in pyramidal neurons of the aged human and rat. ..
- Caunt C, Finch A, Sedgley K, Oakley L, Luttrell L, McArdle C. Arrestin-mediated ERK activation by gonadotropin-releasing hormone receptors: receptor-specific activation mechanisms and compartmentalization. J Biol Chem. 2006;281:2701-10 pubmed
- Hislop J, Caunt C, Sedgley K, Kelly E, Mundell S, Green L, et al. Internalization of gonadotropin-releasing hormone receptors (GnRHRs): does arrestin binding to the C-terminal tail target GnRHRs for dynamin-dependent internalization?. J Mol Endocrinol. 2005;35:177-89 pubmed..Thus, although the C-terminal tail can direct GnRHRs for arrestin- and dynamin-dependent internalization, this effect is not dependent on Src activation and arrestin can also facilitate dynamin-independent internalization. ..
- Knollman P, Conn P. Multiple G proteins compete for binding with the human gonadotropin releasing hormone receptor. Arch Biochem Biophys. 2008;477:92-7 pubmed publisher..Studies were conducted in different human (COS7, HeLa) and rodent-derived (CHO-K1, GH(3)) cell lines in order to confirm that G protein promiscuity observed with the GnRHR was not limited to a particular cell type. ..
- Caunt C, Finch A, Sedgley K, McArdle C. GnRH receptor signalling to ERK: kinetics and compartmentalization. Trends Endocrinol Metab. 2006;17:308-13 pubmed
- Finch A, Caunt C, Armstrong S, McArdle C. Agonist-induced internalization and downregulation of gonadotropin-releasing hormone receptors. Am J Physiol Cell Physiol. 2009;297:C591-600 pubmed publisher..Thus agonist-induced internalization and downregulation of type I mammalian GnRHR occurs in HeLa cells, and we suggest that the high throughput imaging systems described here will facilitate study of the molecular mechanisms involved. ..
- Ikemoto T, Park M. Identification and molecular characterization of three GnRH ligands and five GnRH receptors in the spotted green pufferfish. Mol Cell Endocrinol. 2005;242:67-79 pubmed..Alternative splicing was also observed for some receptor subtypes. The present results indicate that diversified gene expressions combined with molecular diversity contribute to the functional diversity of GnRH. ..
- Pitteloud N, Quinton R, Pearce S, Raivio T, Acierno J, Dwyer A, et al. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest. 2007;117:457-63 pubmed..Therefore, 2 different gene defects can synergize to produce a more severe phenotype in IHH families than either alone. This genetic model could account for some phenotypic heterogeneity seen in GnRH deficiency...
- Brothers S, Cornea A, Janovick J, Conn P. Human loss-of-function gonadotropin-releasing hormone receptor mutants retain wild-type receptors in the endoplasmic reticulum: molecular basis of the dominant-negative effect. Mol Endocrinol. 2004;18:1787-97 pubmed
- Pawson A, Faccenda E, Maudsley S, Lu Z, Naor Z, Millar R. Mammalian type I gonadotropin-releasing hormone receptors undergo slow, constitutive, agonist-independent internalization. Endocrinology. 2008;149:1415-22 pubmed
- Bhagavath B, Layman L. The genetics of hypogonadotropic hypogonadism. Semin Reprod Med. 2007;25:272-86 pubmed
- Ikemoto T, Park M. Comparative analysis of the pituitary and ovarian GnRH systems in the leopard gecko: signaling crosstalk between multiple receptor subtypes in ovarian follicles. J Mol Endocrinol. 2007;38:289-304 pubmed..Seasonal and developmental variations in receptor expression in the anterior pituitary gland and ovarian follicles may contribute to the seasonal breeding of this animal. ..
- Kanda A, Takahashi T, Satake H, Minakata H. Molecular and functional characterization of a novel gonadotropin-releasing-hormone receptor isolated from the common octopus (Octopus vulgaris). Biochem J. 2006;395:125-35 pubmed
- Moncaut N, Somoza G, Power D, Canario A. Five gonadotrophin-releasing hormone receptors in a teleost fish: isolation, tissue distribution and phylogenetic relationships. J Mol Endocrinol. 2005;34:767-79 pubmed
- Karakoula A, Tovey S, Brighton P, Willars G. Lack of receptor-selective effects of either RGS2, RGS3 or RGS4 on muscarinic M3- and gonadotropin-releasing hormone receptor-mediated signalling through G alpha q/11. Eur J Pharmacol. 2008;587:16-24 pubmed publisher..Thus, at least in these circumstances, RGS protein-dependent inhibition of signalling is not influenced by the nature of the G-protein-coupled receptor through which the signalling is mediated. ..
- Millar R, Lu Z, Pawson A, Flanagan C, Morgan K, Maudsley S. Gonadotropin-releasing hormone receptors. Endocr Rev. 2004;25:235-75 pubmed..Delineation of the structural elements in GnRH and the receptor, which facilitate differential signaling, will contribute to the development of novel interventive GnRH analogs. ..
- de Roux N. Isolated gonadotropic deficiency with and without anosmia: a developmental defect or a neuroendocrine regulation abnormality of the gonadotropic axis. Horm Res. 2005;64 Suppl 2:48-55 pubmed..In vivo studies and genotype-phenotype correlations indicate that gonadotropic axis regulation by GPR54 occurs mainly at the level of the hypothalamus...
- Ulloa Aguirre A, Janovick J, Brothers S, Conn P. Pharmacologic rescue of conformationally-defective proteins: implications for the treatment of human disease. Traffic. 2004;5:821-37 pubmed..Special attention is paid to the gonadotropin-releasing hormone receptor, since there is a great deal of information about this receptor, which has recently emerged as a particularly instructive model. ..
- Millar R. GnRHs and GnRH receptors. Anim Reprod Sci. 2005;88:5-28 pubmed..Together, these findings are setting the scene for generating novel selective GnRH analogues with potential for wider and more specific application. ..
- Sedlmeyer I, Pearce C, Trueman J, Butler J, Bersaglieri T, Read A, et al. Determination of sequence variation and haplotype structure for the gonadotropin-releasing hormone (GnRH) and GnRH receptor genes: investigation of role in pubertal timing. J Clin Endocrinol Metab. 2005;90:1091-9 pubmed..We conclude that genetic variation in GNRH1 and GNRHR is not likely to be a substantial modulator of pubertal timing in the general population. ..
- Rodet F, Lelong C, Dubos M, Costil K, Favrel P. Molecular cloning of a molluscan gonadotropin-releasing hormone receptor orthologue specifically expressed in the gonad. Biochim Biophys Acta. 2005;1730:187-95 pubmed..This demonstrates for the first time the plausible involvement of a GnRH receptor orthologue in the control of reproduction in a protostomian invertebrate. ..
- Finch A, Green L, Hislop J, Kelly E, McArdle C. Signaling and antiproliferative effects of type I and II gonadotropin-releasing hormone receptors in breast cancer cells. J Clin Endocrinol Metab. 2004;89:1823-32 pubmed
- Vadakkadath Meethal S, Gallego M, Haasl R, Petras S, Sgro J, Atwood C. Identification of a gonadotropin-releasing hormone receptor orthologue in Caenorhabditis elegans. BMC Evol Biol. 2006;6:103 pubmed..elegans suggests the potential use of C. elegans as a model system to study reproductive endocrinology. ..
- Leaños Miranda A, Ulloa Aguirre A, Janovick J, Conn P. In vitro coexpression and pharmacological rescue of mutant gonadotropin-releasing hormone receptors causing hypogonadotropic hypogonadism in humans expressing compound heterozygous alleles. J Clin Endocrinol Metab. 2005;90:3001-8 pubmed..Depending on the genotype, partial or full restoration of receptor function in response to pharmacological chaperones may be achievable goals in patients bearing inactivating mutations in the GnRHR gene. ..
- Cheng C, Leung P. Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans. Endocr Rev. 2005;26:283-306 pubmed..However, the human type II receptor gene homolog carries a frameshift and a premature stop codon, suggesting that a full-length type II receptor does not exist in humans. ..
- Flanagan C, Chen C, Coetsee M, Mamputha S, Whitlock K, Bredenkamp N, et al. Expression, structure, function, and evolution of gonadotropin-releasing hormone (GnRH) receptors GnRH-R1SHS and GnRH-R2PEY in the teleost, Astatotilapia burtoni. Endocrinology. 2007;148:5060-71 pubmed..Our results suggest that different duplicated GnRH receptor genes have been selected to regulate reproduction in different vertebrate lineages. ..
- Limonta P, Moretti R, Montagnani Marelli M, Motta M. The biology of gonadotropin hormone-releasing hormone: role in the control of tumor growth and progression in humans. Front Neuroendocrinol. 2003;24:279-95 pubmed..The specific biological functions of GnRH-II in humans are presently under investigation. ..
- Neill J, Duck L, Sellers J, Musgrove L. A gonadotropin-releasing hormone (GnRH) receptor specific for GnRH II in primates. Biochem Biophys Res Commun. 2001;282:1012-8 pubmed publisher..This is the first report of a GnRH type II receptor in mammals. Its identification will permit exploration of its role in regulating gonadotropin secretion, female sexual behavior, and tumor cell growth...
- Volker P, Gründker C, Schmidt O, Schulz K, Emons G. Expression of receptors for luteinizing hormone-releasing hormone in human ovarian and endometrial cancers: frequency, autoregulation, and correlation with direct antiproliferative activity of luteinizing hormone-releasing hormone analogues. Am J Obstet Gynecol. 2002;186:171-9 pubmed..Because most respective primary cancers expressed luteinizing hormone-releasing hormone receptors, these receptors might be used for novel antiproliferative therapeutic approaches and should be further evaluated. ..
- Illing N, Troskie B, Nahorniak C, Hapgood J, Peter R, Millar R. Two gonadotropin-releasing hormone receptor subtypes with distinct ligand selectivity and differential distribution in brain and pituitary in the goldfish (Carassius auratus). Proc Natl Acad Sci U S A. 1999;96:2526-31 pubmed..Thus we have found and cloned two full-length cDNAs that appear to correspond to different forms of GnRH receptor, with distinct pharmacological characteristics and tissue distribution, in a single species. ..
- Troskie B, Hapgood J, Millar R, Illing N. Complementary deoxyribonucleic acid cloning, gene expression, and ligand selectivity of a novel gonadotropin-releasing hormone receptor expressed in the pituitary and midbrain of Xenopus laevis. Endocrinology. 2000;141:1764-71 pubmed..laevis GnRH receptor cDNA was chicken GnRH II>salmon GnRH>mammalian GnRH. Transcripts of this GnRH receptor are expressed in the pituitary and midbrain of X. laevis. ..
- Gründker C, Günthert A, Westphalen S, Emons G. Biology of the gonadotropin-releasing hormone system in gynecological cancers. Eur J Endocrinol. 2002;146:1-14 pubmed..Furthermore, GnRH induces activation of the c-Jun N-terminal kinase/activator protein-1 (AP-1) pathway independent of the known AP-1 activators, protein kinase or mitogen activated protein kinase. ..
- Kang S, Tai C, Nathwani P, Leung P. Differential regulation of two forms of gonadotropin-releasing hormone messenger ribonucleic acid in human granulosa-luteal cells. Endocrinology. 2001;142:182-92 pubmed..Taken together, these results suggest that GnRH-II may have biological effects similar to those of GnRH-I but is under differential hormonal regulation in the human ovary. ..
- Sun Y, Dunn I, Baines E, Talbot R, Illing N, Millar R, et al. Distribution and regulation by oestrogen of fully processed and variant transcripts of gonadotropin releasing hormone I and gonadotropin releasing hormone receptor mRNAs in the male chicken. J Neuroendocrinol. 2001;13:37-49 pubmed..Oestrogen appears to play a role in the regulation of cGnRH Ia and b in the POA and testes, and of cGnRH-Ra in the POA and anterior pituitary gland. ..
- Leaños Miranda A, Janovick J, Conn P. Receptor-misrouting: an unexpectedly prevalent and rescuable etiology in gonadotropin-releasing hormone receptor-mediated hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2002;87:4825-8 pubmed..A classification system for GnRHR mutants is proposed. ..
- Otsuka F, Shimasaki S. A novel function of bone morphogenetic protein-15 in the pituitary: selective synthesis and secretion of FSH by gonadotropes. Endocrinology. 2002;143:4938-41 pubmed..These findings, together with the previous evidence of a negative regulation of FSH receptor expression by BMP-15 in the ovary, may constitute a major role in female fertility. ..
- Pfleger K, Bogerd J, Millar R. Conformational constraint of mammalian, chicken, and salmon GnRHs, but not GnRH II, enhances binding at mammalian and nonmammalian receptors: evidence for preconfiguration of GnRH II. Mol Endocrinol. 2002;16:2155-62 pubmed..We suggest that this ligand is preconfigured through intramolecular interactions, which accounts for its high binding affinity and total conservation of primary structure over 500 million years of evolution. ..
- Moretti R, Monagnani Marelli M, van Groeninghen J, Motta M, Limonta P. Inhibitory activity of luteinizing hormone-releasing hormone on tumor growth and progression. Endocr Relat Cancer. 2003;10:161-7 pubmed..We have demonstrated that both LHRH and LHRH receptors are expressed in human melanoma cells (BLM and Me15392)...
- Brothers S, Janovick J, Conn P. Unexpected effects of epitope and chimeric tags on gonadotropin-releasing hormone receptors: implications for understanding the molecular etiology of hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2003;88:6107-12 pubmed..Although rarely provided, control experiments addressing the effects of epitope or chimeric tagging are an essential part of any study relying on these proteomic tools. ..
- Janovick J, Ulloa Aguirre A, Conn P. Evolved regulation of gonadotropin-releasing hormone receptor cell surface expression. Endocrine. 2003;22:317-27 pubmed..The data further reveal that additional modifications must have occurred in primates that are important for both the diminution of the PME and the development of the dominant negative effect of the mutants. ..
- Janovick J, Maya Nunez G, Conn P. Rescue of hypogonadotropic hypogonadism-causing and manufactured GnRH receptor mutants by a specific protein-folding template: misrouted proteins as a novel disease etiology and therapeutic target. J Clin Endocrinol Metab. 2002;87:3255-62 pubmed..The present findings demonstrate the efficacy of an approach based on pharmacological rescue and suggest the basis of new approaches for intervention in this and similar diseases. ..
- Janovick J, Goulet M, Bush E, Greer J, Wettlaufer D, Conn P. Structure-activity relations of successful pharmacologic chaperones for rescue of naturally occurring and manufactured mutants of the gonadotropin-releasing hormone receptor. J Pharmacol Exp Ther. 2003;305:608-14 pubmed..The ability to rescue a particular receptor was a reasonable predictor of the ability to rescue others, even across species lines, although particular mutants could not be rescued by any of the drugs tested. ..