Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Mol Endocrinol
2010 Feb 01;242:423-35. doi: 10.1210/me.2009-0343.
Show Gene links
Show Anatomy links
Plasma membrane expression of gonadotropin-releasing hormone receptors: regulation by peptide and nonpeptide antagonists.
Finch AR
,
Caunt CJ
,
Armstrong SP
,
McArdle CA
.
???displayArticle.abstract???
Gonadotropin-releasing hormone acts via cell surface receptors but most human (h) GnRH receptors (GnRHRs) are intracellular. A membrane-permeant nonpeptide antagonist [(2S)-2-[5-[2-(2-axabicyclo[2.2.2]oct-2-yl)-1,1-dimethy-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-N-(2-pyridin-4-ylethyl)propan-1-amine (IN3)] increases hGnRHR expression at the surface, apparently by facilitating its exit from the endoplasmic reticulum. Here we have quantified GnRHR by automated imaging in HeLa cells transduced with adenovirus expressing hemagglutinin-tagged GnRHR. Consistent with an intracellular site of action, IN3 increases cell surface hGnRHR, and this effect is not blocked or mimicked by membrane-impermeant peptide antagonists [Ac-D2Nal-D4Cpa-D3Pal-Ser-Tyr-d-Cit-Leu-Arg-Pro-d-Ala-NH(2) (cetrorelix) and antide]. However, when the C-terminal tail of a Xenopus (X) GnRHR was added (h.XGnRHR) to increase expression, both peptides further increased cell surface GnRHR. Cetrorelix also synergized with IN3 to increase expression of hGnRHR and a G-protein coupling-deficient mutant (A261K-hGnRHR). Cetrorelix also increased cell surface expression of hGnRHR, h.XGnRHR, and mouse GnRHR in gonadotrope-lineage LbetaT2 cells, and in HeLa cells it slowed h.XGnRHR internalization (measured by receptor-mediated antihemagglutinin uptake). Thus cetrorelix has effects other than GnRHR blockade; it acts as an inverse agonist in internalization assays, supporting the potential importance of ligand-biased efficacy at GnRHR. We also developed an imaging assay for GnRH function based on Ca(2+)-dependent nuclear translocation of a nuclear factor of activated T cells reporter. Using this in HeLa and LbetaT2 cells, IN3 and cetrorelix behaved as competitive antagonists when coincubated with GnRH, and long-term pretreatment (16 h) with IN3 reduced its effectiveness as an inhibitor whereas pretreatment with cetrorelix increased its inhibitory effect. This distinction between peptide and nonpeptide antagonists may prove important for therapeutic applications of GnRH antagonists.
Bernier,
Pharmacological chaperones: potential treatment for conformational diseases.
2004, Pubmed
Bernier,
Pharmacological chaperones: potential treatment for conformational diseases.
2004,
Pubmed
Betz,
Non-peptide gonadotropin-releasing hormone receptor antagonists.
2008,
Pubmed
Blithe,
Applications for GnRH antagonists.
2001,
Pubmed
Blomenröhr,
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.
1999,
Pubmed
Caunt,
Regulation of gonadotropin-releasing hormone receptors by protein kinase C: inside out signalling and evidence for multiple active conformations.
2004,
Pubmed
,
Xenbase
Cheng,
Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans.
2005,
Pubmed
Conn,
The molecular mechanism of action of gonadotropin releasing hormone (GnRH) in the pituitary.
1987,
Pubmed
Conn,
Protein folding as posttranslational regulation: evolution of a mechanism for controlled plasma membrane expression of a G protein-coupled receptor.
2006,
Pubmed
Conn,
G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo.
2007,
Pubmed
Davidson,
Absence of rapid desensitization of the mouse gonadotropin-releasing hormone receptor.
1994,
Pubmed
Davidson,
Identification of N-glycosylation sites in the gonadotropin-releasing hormone receptor: role in receptor expression but not ligand binding.
1995,
Pubmed
Emons,
Effects of LHRH-analogues on mitogenic signal transduction in cancer cells.
1998,
Pubmed
Finch,
Agonist-induced internalization and downregulation of gonadotropin-releasing hormone receptors.
2009,
Pubmed
,
Xenbase
Finch,
Plasma membrane expression of GnRH receptors: regulation by antagonists in breast, prostate, and gonadotrope cell lines.
2008,
Pubmed
,
Xenbase
Heding,
Gonadotropin-releasing hormone receptors with intracellular carboxyl-terminal tails undergo acute desensitization of total inositol phosphate production and exhibit accelerated internalization kinetics.
1998,
Pubmed
Heitman,
Amiloride derivatives and a nonpeptidic antagonist bind at two distinct allosteric sites in the human gonadotropin-releasing hormone receptor.
2008,
Pubmed
Hislop,
Differential internalization of mammalian and non-mammalian gonadotropin-releasing hormone receptors. Uncoupling of dynamin-dependent internalization from mitogen-activated protein kinase signaling.
2001,
Pubmed
,
Xenbase
Kohout,
Trapping of a nonpeptide ligand by the extracellular domains of the gonadotropin-releasing hormone receptor results in insurmountable antagonism.
2007,
Pubmed
Kopito,
Conformational disease.
2000,
Pubmed
Lin,
Addition of catfish gonadotropin-releasing hormone (GnRH) receptor intracellular carboxyl-terminal tail to rat GnRH receptor alters receptor expression and regulation.
1998,
Pubmed
Luttrell,
The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals.
2002,
Pubmed
López de Maturana,
Gonadotropin-releasing hormone analog structural determinants of selectivity for inhibition of cell growth: support for the concept of ligand-induced selective signaling.
2008,
Pubmed
Macian,
NFAT proteins: key regulators of T-cell development and function.
2005,
Pubmed
Maudsley,
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.
2004,
Pubmed
McArdle,
Signalling, cycling and desensitisation of gonadotrophin-releasing hormone receptors.
2002,
Pubmed
,
Xenbase
McArdle,
Desensitization of gonadotropin-releasing hormone action in the gonadotrope-derived alpha T3-1 cell line.
1995,
Pubmed
McArdle,
Desensitization of gonadotropin-releasing hormone action in alphaT3-1 cells due to uncoupling of inositol 1,4,5-trisphosphate generation and Ca2+ mobilization.
1996,
Pubmed
Millar,
Gonadotropin-releasing hormone receptors.
2004,
Pubmed
Myburgh,
Alanine-261 in intracellular loop III of the human gonadotropin-releasing hormone receptor is crucial for G-protein coupling and receptor internalization.
1998,
Pubmed
Pawson,
Contrasting internalization kinetics of human and chicken gonadotropin-releasing hormone receptors mediated by C-terminal tail.
1998,
Pubmed
Petaja-Repo,
Export from the endoplasmic reticulum represents the limiting step in the maturation and cell surface expression of the human delta opioid receptor.
2000,
Pubmed
Petäjä-Repo,
Ligands act as pharmacological chaperones and increase the efficiency of delta opioid receptor maturation.
2002,
Pubmed
Pierce,
Seven-transmembrane receptors.
2002,
Pubmed
Rispoli,
Pituitary gonadotropin-releasing hormone (GnRH) receptor: structure, distribution and regulation of expression.
2005,
Pubmed
Sedgley,
Intracellular gonadotropin-releasing hormone receptors in breast cancer and gonadotrope lineage cells.
2006,
Pubmed
,
Xenbase
Stojilkovic,
Expression and signal transduction pathways of gonadotropin-releasing hormone receptors.
1995,
Pubmed
Tan,
Membrane trafficking of G protein-coupled receptors.
2004,
Pubmed
Ulloa-Aguirre,
Pharmacologic rescue of conformationally-defective proteins: implications for the treatment of human disease.
2004,
Pubmed
Zhang,
Role of delivery and trafficking of delta-opioid peptide receptors in opioid analgesia and tolerance.
2006,
Pubmed