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Endocrine Reviews 18 (2): 180-205
Copyright © 1997 by The Endocrine Society

Molecular Mechanisms of Ligand Interaction with the Gonadotropin-Releasing Hormone Receptor

Stuart C. Sealfon, Harel Weinstein and Robert P. Millar

Fishberg Research Center in Neurobiology (S.C.S.), Departments of Neurology (S.C.S.), Physiology and Biophysics (H.W.), and Pharmacology (H. W.), Mount Sinai School of Medicine, New York, New York 10029; and Medical Research Council Regulatory Peptides Unit (R.P.M.), Departments of Chemical Pathology (R.P.M.) and Medicine (R.P.M.), University of Cape Town Medical School, Observatory 7925, South Africa

I. Introduction
II. Amino Acid Sequences of GnRH Receptors
A. GnRH receptor cDNAs
B. General structural features
C. Covalent modifications
D. Gene structure
III. Structure-Activity Relations of GnRH Peptides
A. Overview
B. Comparative structures and activities of vertebrate GnRHs
C. Roles of individual amino acids in GnRH activity at the mammalian receptor
D. Conclusions from peptide structure-activity data
IV. Structure and Conformation of GnRH and Its Analogs
A. Early studies of GnRH conformation
B. Integrated computational and experimental studies
C. Exploration of the entire conformation space of GnRH analogs
V. Functional Structure of the Receptor and Ligand-Receptor Complex
A. Extracellular domains
B. Helix domains
C. Intracellular loop domains
D. Computational modeling of three-dimensional receptor structure
VI. Conclusions




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V. D. Dixit, R. Sridaran, M. A. Edmonsond, D. Taub, and W. E. Thompson
Gonadotropin-Releasing Hormone Attenuates Pregnancy-Associated Thymic Involution and Modulates the Expression of Antiproliferative Gene Product Prohibitin
Endocrinology, April 1, 2003; 144(4): 1496 - 1505.
[Abstract] [Full Text] [PDF]

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K. Morgan, D. Conklin, A. J. Pawson, R. Sellar, T. R. Ott, and R. P. Millar
A Transcriptionally Active Human Type II Gonadotropin-Releasing Hormone Receptor Gene Homolog Overlaps Two Genes in the Antisense Orientation on Chromosome 1q.12
Endocrinology, February 1, 2003; 144(2): 423 - 436.
[Abstract] [Full Text] [PDF]

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J. Y. Seong, L. Wang, D. Y. Oh, O. Yun, K. Maiti, J. H. Li, J. M. Soh, H. S. Choi, K. Kim, H. Vaudry, et al.
Ala/Thr201 in Extracellular Loop 2 and Leu/Phe290 in Transmembrane Domain 6 of Type 1 Frog Gonadotropin-Releasing Hormone Receptor Confer Differential Ligand Sensitivity and Signal Transduction
Endocrinology, February 1, 2003; 144(2): 454 - 466.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
D. Harris, D. Chuderland, D. Bonfil, S. Kraus, R. Seger, and Z. Naor
Extracellular Signal-Regulated Kinase and c-Src, But Not Jun N-Terminal Kinase, Are Involved in Basal and Gonadotropin-Releasing Hormone-Stimulated Activity of the Glycoprotein Hormone {alpha}-Subunit Promoter
Endocrinology, February 1, 2003; 144(2): 612 - 622.
[Abstract] [Full Text] [PDF]

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E. Terasawa
Gonadotropin-Releasing Hormone II: Is this Neuropeptide Important for Mammalian Reproduction?
Endocrinology, January 1, 2003; 144(1): 3 - 4.
[Full Text] [PDF]

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 J. Biol. Chem.Home page
C. Prioleau, I. Visiers, B. J. Ebersole, H. Weinstein, and S. C. Sealfon
Conserved Helix 7 Tyrosine Acts as a Multistate Conformational Switch in the 5HT2C Receptor. IDENTIFICATION OF A NOVEL "LOCKED-ON" PHENOTYPE AND DOUBLE REVERTANT MUTATIONS
J. Biol. Chem., September 20, 2002; 277(39): 36577 - 36584.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
K. D. G. Pfleger, J. Bogerd, and R. P. Millar
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., September 1, 2002; 16(9): 2155 - 2162.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
L. F. G. Silveira, P. M. Stewart, M. Thomas, D. A. Clark, P. M. G. Bouloux, and G. S. MacColl
Novel Homozygous Splice Acceptor Site GnRH Receptor (GnRHR) Mutation: Human GnRHR "Knockout"
J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2973 - 2977.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
G. Maya-Nunez, J. A. Janovick, A. Ulloa-Aguirre, D. Soderlund, P. M. Conn, and J. P. Mendez
Molecular Basis of Hypogonadotropic Hypogonadism: Restoration of Mutant (E90K) GnRH Receptor Function by a Deletion at a Distant Site
J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2144 - 2149.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
T. R. Ott, B. E. Troskie, R. W. Roeske, N. Illing, C. A. Flanagan, and R. P. Millar
Two Mutations in Extracellular Loop 2 of the Human GnRH Receptor Convert an Antagonist to an Agonist
Mol. Endocrinol., May 1, 2002; 16(5): 1079 - 1088.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
D. Grove-Strawser, S. A. Sower, P. M. Ronsheim, J. B. Connolly, C. G. Bourn, and B. S. Rubin
Guinea Pig GnRH: Localization and Physiological Activity Reveal That It, Not Mammalian GnRH, Is the Major Neuroendocrine Form in Guinea Pigs
Endocrinology, May 1, 2002; 143(5): 1602 - 1612.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
C. Castro-Fernandez, J. A. Janovick, S. P. Brothers, R. A. Fisher, T. H. Ji, and P. M. Conn
Regulation of RGS3 and RGS10 Palmitoylation by GnRH
Endocrinology, April 1, 2002; 143(4): 1310 - 1317.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
D. Pati and H. R. Habibi
Involvement of Protein Kinase C and Arachidonic Acid Pathways in the Gonadotropin-Releasing Hormone Regulation of Oocyte Meiosis and Follicular Steroidogenesis in the Goldfish Ovary
Biol Reprod, March 1, 2002; 66(3): 813 - 822.
[Abstract] [Full Text] [PDF]

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 Mol. Pharmacol.Home page
B. J. Fromme, A. A. Katz, R. W. Roeske, R. P. Millar, and C. A. Flanagan
Role of Aspartate7.32(302) of the Human Gonadotropin-Releasing Hormone Receptor in Stabilizing a High-Affinity Ligand Conformation
Mol. Pharmacol., December 1, 2001; 60(6): 1280 - 1287.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
H. M. Everest, J. N. Hislop, T. Harding, J. B. Uney, A. Flynn, R. P. Millar, and C. A. McArdle
Signaling and Antiproliferative Effects Mediated by GnRH Receptors After Expression in Breast Cancer Cells Using Recombinant Adenovirus
Endocrinology, November 1, 2001; 142(11): 4663 - 4672.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. N. Hislop, H. M. Everest, A. Flynn, T. Harding, J. B. Uney, B. E. Troskie, R. P. Millar, and C. A. McArdle
Differential Internalization of Mammalian and Non-mammalian Gonadotropin-releasing Hormone Receptors. UNCOUPLING OF DYNAMIN-DEPENDENT INTERNALIZATION FROM MITOGEN-ACTIVATED PROTEIN KINASE SIGNALING
J. Biol. Chem., October 19, 2001; 276(43): 39685 - 39694.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
L. Wang, D. Y. Oh, J. Bogerd, H. S. Choi, R. S. Ahn, J. Y. Seong, and H. B. Kwon
Inhibitory Activity of Alternative Splice Variants of the Bullfrog GnRH Receptor-3 on Wild-Type Receptor Signaling
Endocrinology, September 1, 2001; 142(9): 4015 - 4025.
[Abstract] [Full Text] [PDF]

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 J. Neurosci.Home page
F. Van Goor, Y.-X. Li, and S. S. Stojilkovic
Paradoxical Role of Large-Conductance Calcium-Activated K+ (BK) Channels in Controlling Action Potential-Driven Ca2+ Entry in Anterior Pituitary Cells
J. Neurosci., August 15, 2001; 21(16): 5902 - 5915.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
R. Millar, S. Lowe, D. Conklin, A. Pawson, S. Maudsley, B. Troskie, T. Ott, M. Millar, G. Lincoln, R. Sellar, et al.
A novel mammalian receptor for the evolutionarily conserved type II GnRH
PNAS, August 1, 2001; (2001) 141048498.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
R. D. Horvat, D. A. Roess, S. E. Nelson, B. G. Barisas, and C. M. Clay
Binding of Agonist but Not Antagonist Leads to Fluorescence Resonance Energy Transfer between Intrinsically Fluorescent Gonadotropin-Releasing Hormone Receptors
Mol. Endocrinol., May 1, 2001; 15(5): 695 - 703.
[Abstract] [Full Text]

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 Mol Hum ReprodHome page
K. W. Cheon, H.-S. Lee, I. S. Parhar, and I. S. Kang
Expression of the second isoform of gonadotrophin-releasing hormone (GnRH-II) in human endometrium throughout the menstrual cycle
Mol. Hum. Reprod., May 1, 2001; 7(5): 447 - 452.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
L. Wang, J. Bogerd, H. S. Choi, J. Y. Seong, J. M. Soh, S. Y. Chun, M. Blomenröhr, B. E. Troskie, R. P. Millar, W. H. Yu, et al.
Three distinct types of GnRH receptor characterized in the bullfrog
PNAS, December 14, 2000; (2000) 11508498.
[Abstract] [Full Text]

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 EndocrinologyHome page
J. N. Hislop, M. T. Madziva, H. M. Everest, T. Harding, J. B. Uney, G. B. Willars, R. P. Millar, B. E. Troskie, J. S. Davidson, and C. A. McArdle
Desensitization and Internalization of Human and XenopusGonadotropin-Releasing Hormone Receptors Expressed in {{alpha}}T4 Pituitary Cells Using Recombinant Adenovirus
Endocrinology, December 1, 2000; 141(12): 4564 - 4575.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
T. Madigou, E. Mañanos-Sanchez, S. Hulshof, I. Anglade, S. Zanuy, and O. Kah
Cloning, Tissue Distribution, and Central Expression of the Gonadotropin-Releasing Hormone Receptor in the Rainbow Trout (Oncorhynchus mykiss)
Biol Reprod, December 1, 2000; 63(6): 1857 - 1866.
[Abstract] [Full Text]

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 Mol. Endocrinol.Home page
R. Sosnowski, P. L. Mellon, and M. A. Lawson
Activation of Translation in Pituitary Gonadotrope Cells by Gonadotropin-Releasing Hormone
Mol. Endocrinol., November 1, 2000; 14(11): 1811 - 1819.
[Abstract] [Full Text]

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 Mol. Endocrinol.Home page
S. H. Hoffmann, T. t. Laak, R. Kühne, H. Reiländer, and T. Beckers
Residues within Transmembrane Helices 2 and 5 of the Human Gonadotropin-Releasing Hormone Receptor Contribute to Agonist and Antagonist Binding
Mol. Endocrinol., July 1, 2000; 14(7): 1099 - 1115.
[Abstract] [Full Text]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
F. E. M. Rebers, P. T. Bosma, W. van Dijk, H. J. T. Goos, and R. W. Schulz
GnRH stimulates LH release directly via inositol phosphate and indirectly via cAMP in African catfish
Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2000; 278(6): R1572 - R1578.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
J. Cui, R. G. Smith, G. R. Mount, J.-L. Lo, J. Yu, T. F. Walsh, S. B. Singh, R. J. DeVita, M. T. Goulet, J. M. Schaeffer, et al.
Identification of Phe313 of the Gonadotropin-Releasing Hormone (GnRH) Receptor as a Site Critical for the Binding of Nonpeptide GnRH Antagonists
Mol. Endocrinol., May 1, 2000; 14(5): 671 - 681.
[Abstract] [Full Text]

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 EndocrinologyHome page
B. E. Troskie, J. P. Hapgood, R. P. Millar, and N. Illing
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, May 1, 2000; 141(5): 1764 - 1771.
[Abstract] [Full Text] [PDF]

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J. Carolsfeld, J. F. F. Powell, M. Park, W. H. Fischer, A. G. Craig, J. P. Chang, J. E. Rivier, and N. M. Sherwood
Primary Structure and Function of Three Gonadotropin-Releasing Hormones, Including a Novel Form, from an Ancient Teleost, Herring
Endocrinology, February 1, 2000; 141(2): 505 - 512.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
H.-O. Chung, Q. Yang, K. J. Catt, and K. K. Arora
Expression and Function of the Gonadotropin-releasing Hormone Receptor Are Dependent on a Conserved Apolar Amino Acid in the Third Intracellular Loop
J. Biol. Chem., December 10, 1999; 274(50): 35756 - 35762.
[Abstract] [Full Text] [PDF]

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 Mol. Pharmacol.Home page
M. Blomenröhr, A. Heding, R. Sellar, R. Leurs, J. Bogerd, K. A. Eidne, and G. B. Willars
Pivotal Role for the Cytoplasmic Carboxyl-Terminal Tail of a Nonmammalian Gonadotropin-Releasing Hormone Receptor in Cell Surface Expression, Ligand Binding, and Receptor Phosphorylation and Internalization
Mol. Pharmacol., December 1, 1999; 56(6): 1229 - 1237.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
C. A. Flanagan, W. Zhou, L. Chi, T. Yuen, V. Rodic, D. Robertson, M. Johnson, P. Holland, R. P. Millar, H. Weinstein, et al.
The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor
J. Biol. Chem., October 8, 1999; 274(41): 28880 - 28886.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
F. P. Pralong, F. Gomez, E. Castillo, S. Cotecchia, L. Abuin, M. L. Aubert, L. Portmann, and R. C. Gaillard
Complete Hypogonadotropic Hypogonadism Associated with a Novel Inactivating Mutation of the Gonadotropin-Releasing Hormone Receptor
J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3811 - 3816.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
K. K. Arora, H.-O. Chung, and K. J. Catt
Influence of a Species-Specific Extracellular Amino Acid on Expression and Function of the Human Gonadotropin-Releasing Hormone Receptor
Mol. Endocrinol., June 1, 1999; 13(6): 890 - 896.
[Abstract] [Full Text]

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 EndocrinologyHome page
J. D. Neill, L. C. Musgrove, L. W. Duck, and J. C. Sellers
High Efficiency Method for Gene Transfer in Normal Pituitary Gonadotropes: Adenoviral-Mediated Expression of G Protein-Coupled Receptor Kinase 2 Suppresses Luteinizing Hormone Secretion
Endocrinology, June 1, 1999; 140(6): 2562 - 2569.
[Abstract] [Full Text]

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 Proc. Natl. Acad. Sci. USAHome page
N. Illing, B. E. Troskie, C. S. Nahorniak, J. P. Hapgood, R. E. Peter, and R. P. Millar
Two gonadotropin-releasing hormone receptor subtypes with distinct ligand selectivity and differential distribution in brain and pituitary in the goldfish (Carassius auratus)
PNAS, March 2, 1999; 96(5): 2526 - 2531.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
S. Nelson, R. D. Horvat, J. Malvey, D. A. Roess, B. G. Barisas, and C. M. Clay
Characterization of an Intrinsically Fluorescent Gonadotropin-Releasing Hormone Receptor and Effects of Ligand Binding on Receptor Lateral Diffusion
Endocrinology, February 1, 1999; 140(2): 950 - 957.
[Abstract] [Full Text]

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 EndocrinologyHome page
X. Lin and P. M. Conn
Transcriptional Activation of Gonadotropin-Releasing Hormone (GnRH) Receptor Gene by GnRH: Involvement of Multiple Signal Transduction Pathways
Endocrinology, January 1, 1999; 140(1): 358 - 364.
[Abstract] [Full Text]

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 Biol. Reprod.Home page
X. Lin, J. A. Janovick, and P. M. Conn
Mutations at the Consensus Phosphorylation Sites in the Third Intracellular Loop of the Rat Gonadotropin-Releasing Hormone Receptor: Effects on Receptor Ligand Binding and Signal Transduction
Biol Reprod, December 1, 1998; 59(6): 1470 - 1476.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
K. K. Arora, L. Z. Krsmanovic, N. Mores, H. O'Farrell, and K. J. Catt
Mediation of Cyclic AMP Signaling by the First Intracellular Loop of the Gonadotropin-releasing Hormone Receptor
J. Biol. Chem., October 2, 1998; 273(40): 25581 - 25586.
[Abstract] [Full Text] [PDF]


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