Robert P. Millar,
Zhi-Liang Lu,
Adam J. Pawson,
Colleen A. Flanagan,
Kevin Morgan and
Stuart R. Maudsley
Medical Research Council Human Reproductive Sciences Unit (R.P.M., Z.-L.L., A.J.P., K.M., S.R.M.), Centre for Reproductive Biology, Edinburgh EH16 4SB, Scotland, United Kingdom; and Division of Medical Biochemistry and Department of Medicine (R.P.M., C.A.F.), University of Cape Town Faculty of Health Sciences, Cape Town 7925, South Africa
Correspondence: Address all correspondence and requests for reprints to: Professor Robert P. Millar, Medical Research Council Human Reproductive Sciences Unit, The Chancellor’s Building, 49 Little France Crescent, Edinburgh EH16 4SB, Scotland, United Kingdom. E-mail: r.millar{at}hrsu.mrc.ac.uk
GnRH and its analogs are used extensively for the treatmentof hormone-dependent diseases and assisted reproductive techniques.They also have potential as novel contraceptives in men andwomen. A thorough delineation of the molecular mechanisms involvedin ligand binding, receptor activation, and intracellular signaltransduction is kernel to understanding disease processes andthe development of specific interventions. Twenty-three structuralvariants of GnRH have been identified in protochordates andvertebrates. In many vertebrates, three GnRHs and three cognatereceptors have been identified with distinct distributions andfunctions. In man, the hypothalamic GnRH regulates gonadotropinsecretion through the pituitary GnRH type I receptor via activationof Gq. In-depth studies have identified amino acid residuesin both the ligand and receptor involved in binding, receptoractivation, and translation into intracellular signal transduction.Although the predominant coupling of the type I GnRH receptorin the gonadotrope is through productive Gq stimulation, signaltransduction can occur via other G proteins and potentiallyby G protein-independent means. The eventual selection of intracellularsignaling may be specifically directed by variations in ligandstructure. A second form of GnRH, GnRH II, conserved in allhigher vertebrates, including man, is present in extrahypothalamicbrain and many reproductive tissues. Its cognate receptor hasbeen cloned from various vertebrate species, including New andOld World primates. The human gene homolog of this receptor,however, has a frame-shift and stop codon, and it appears thatGnRH II signaling occurs through the type I GnRH receptor. Therehas been considerable plasticity in the use of different GnRHs,receptors, and signaling pathways for diverse functions. Delineationof the structural elements in GnRH and the receptor, which facilitatedifferential signaling, will contribute to the development ofnovel interventive GnRH analogs.
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J. Biol. Chem.,
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[Abstract][Full Text][PDF]
M. R. Silver, N. V. Nucci, A. R. Root, K. L. Reed, and S. A. Sower Cloning and Characterization of a Functional Type II Gonadotropin-Releasing Hormone Receptor with a Lengthy Carboxy-Terminal Tail from an Ancestral Vertebrate, the Sea Lamprey
Endocrinology,
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[Abstract][Full Text][PDF]
P. E. Knollman, J. A. Janovick, S. P. Brothers, and P. M. Conn Parallel Regulation of Membrane Trafficking and Dominant-negative Effects by Misrouted Gonadotropin-releasing Hormone Receptor Mutants
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N. Moncaut, G. Somoza, D. M Power, and A. V M Canario Five gonadotrophin-releasing hormone receptors in a teleost fish: isolation, tissue distribution and phylogenetic relationships
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[Abstract][Full Text][PDF]
A. J. Pawson, S. Maudsley, K. Morgan, L. Davidson, Z. Naor, and R. P. Millar Inhibition of Human Type I Gonadotropin-Releasing Hormone Receptor (GnRHR) Function by Expression of a Human Type II GnRHR Gene Fragment
Endocrinology,
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[Abstract][Full Text][PDF]
M. M. Grumbach A Window of Opportunity: The Diagnosis of Gonadotropin Deficiency in the Male Infant
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A. Leanos-Miranda, A. Ulloa-Aguirre, J. A. Janovick, and P. M. Conn In Vitro Coexpression and Pharmacological Rescue of Mutant Gonadotropin-Releasing Hormone Receptors Causing Hypogonadotropic Hypogonadism in Humans Expressing Compound Heterozygous Alleles
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V. M. Navarro, J. M. Castellano, R. Fernandez-Fernandez, S. Tovar, J. Roa, A. Mayen, M. L. Barreiro, F. F. Casanueva, E. Aguilar, C. Dieguez, et al. Effects of KiSS-1 Peptide, the Natural Ligand of GPR54, on Follicle-Stimulating Hormone Secretion in the Rat
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J. H. Li, H. Choe, A. F. Wang, K. Maiti, C. Wang, A. Salam, S. Y. Chun, W.-K. Lee, K. Kim, H. B. Kwon, et al. Extracellular Loop 3 (EL3) and EL3-Proximal Transmembrane Helix 7 of the Mammalian Type I and Type II Gonadotropin-Releasing Hormone (GnRH) Receptors Determine Differential Ligand Selectivity to GnRH-I and GnRH-II
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[Abstract][Full Text][PDF]
K.-Y. Kim, K.-C. Choi, S.-H. Park, N. Auersperg, and P. C. K. Leung Extracellular Signal-Regulated Protein Kinase, But Not c-Jun N-Terminal Kinase, Is Activated by Type II Gonadotropin-Releasing Hormone Involved in the Inhibition of Ovarian Cancer Cell Proliferation
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I. S. Parhar, S. Ogawa, and Y. Sakuma Three GnRH receptor types in laser-captured single cells of the cichlid pituitary display cellular and functional heterogeneity
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[Abstract][Full Text][PDF]
S. Maudsley, L. Davidson, A. J. Pawson, R. Chan, R. L. de Maturana, and R. P. Millar Gonadotropin-Releasing Hormone (GnRH) Antagonists Promote Proapoptotic Signaling in Peripheral Reproductive Tumor Cells by Activating a G{alpha}i-Coupling State of the Type I GnRH Receptor
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[Abstract][Full Text][PDF]
R. P. Millar and A. J. Pawson Outside-In and Inside-Out Signaling: The New Concept that Selectivity of Ligand Binding at the Gonadotropin-Releasing Hormone Receptor Is Modulated by the Intracellular Environment
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