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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of a GnRH antagonist analogue (N-acetyl-Ala1,D-p-Cl-Phe2,D-Trp3,6-GnRH, Ant.) and a GnRH antiserum (A/S) on the development of pituitary-testicular function were studied in immature (23/24-31/32-day-old) rats. In another experiment the Ant. treatment was combined with bromocriptine (BR)-induced hypoprolactinaemia. Ant. and A/S decreased serum and pituitary levels of LH and FSH, and BR those of Prl (P less than 0.01-0.05). Testicular testosterone (T) and progesterone (P) contents were significantly decreased only by Ant. (P less than 0.01). Ant. decreased the weights of the testes, ventral prostates and seminal vesicles, as well as testicular LH, FSH and Prl receptors (R) (P less than 0.01-0.05). BR decreased LH-R but had no effect on Prl-R. Both Ant. and A/S decreased available pituitary GnRH-R (P less than 0.01), but free testicular GnRH-R were reduced only by Ant. BR increased GnRH receptors in the pituitaries. It is concluded that Ant.-induced low gonadotropin levels in immature animals inhibit the developmental increase of testicular weight, gonadotropin and Prl-R, steroidogenesis and androgen action on accessory sex glands. Hypoprolactinaemia had an additive inhibitory effect to the antigonadal effects of Ant. The testis tissue of immature (23/24-day-old) animals already contains GnRH-R. In general, developing animals are clearly very sensitive to the antigonadal actions of Ant. and BR, whereas the effect of GnRH-A/S is less pronounced than in adults.
Mol Cell Endocrinol 1984 Feb
PMID:Pituitary-testicular function in immature rats after treatment with GnRH antagonist, GnRH antiserum and bromocriptine. 632 70

We examined the functional significance of two residues present in the second (Asp100) and seventh (Asn391) transmembrane domains of the rat cholecystokininB (CCKB) receptor that are highly conserved among the members of the G protein-coupled receptor family. Substitution of Asn for Asp100 by using site-directed mutagenesis did not change the affinity and selectivity for agonists but slightly increased the affinity of three CCKB-selective antagonists of different chemical structures. Cells expressing the mutant receptor exhibited a 50% reduction in CCKB-induced phosphoinositide turnover compared with cells expressing the wild-type receptor, suggesting a critical role for this residue in the coupling of the CCKB receptor to G protein. This latter was shown to be insensitive to pertussis toxin treatment and could therefore belong to the Gq family. Replacement of Asn391 by Asp located in the seventh transmembrane domain did not change agonist binding or phosphoinositide turnover. This suggests that in contrast to the gonadotropin-releasing hormone receptor, there is no direct interaction in the CCKB receptor between Asp100 and Asn391. However, a rhodopsin-based molecular modeling of the CCKB receptor showed a spatial proximity between Asp100 and the carboxyl terminal part of the third intracellular loop, known to interact with G protein. This could explain the reduction in phosphoinositide turnover observed with the Asn100 mutant.
Mol Pharmacol 1995 Nov
PMID:Mutation of Asp100 in the second transmembrane domain of the cholecystokinin B receptor increases antagonist binding and reduces signal transduction. 747 7

TRH and GnRH receptors are each coupled to G proteins of the Gq/11 family. Activation of each of these receptors by their respective ligands results in the stimulation of phospholipase C activity, leading to calcium mobilization and protein kinase C activation. Thus, the effects of TRH and GnRH may be mediated through the same intracellular signal transduction pathway. To compare responses to TRH and GnRH directly within one cell type, we have stably transfected the rat pituitary GH3 lactotrope cell line, which expresses the endogenous TRH receptor, with an expression vector containing rat GnRH receptor cDNA. Transfected cells specifically bound GnRH with high affinity and responded to GnRH stimulation with an increase in PRL mRNA levels, analogous to their response to TRH stimulation. Stably transfected GH3 cells, which were then transiently transfected with luciferase reporter constructs containing either the PRL or the glycoprotein hormone alpha-subunit promoter, responded to either GnRH or TRH stimulation with an increase in luciferase activity in a time- and dose-dependent fashion. The stimulatory effects of maximally effective concentrations of TRH and GnRH were additive on PRL, but not alpha-subunit, gene expression. These data, coupled with evidence of cross-desensitization of alpha-subunit, but not PRL, promoter activity stimulation by TRH and GnRH, suggest that there may be differences in the signal transduction pathways activated by TRH and GnRH receptors in the regulation of PRL and alpha-subunit gene expression.
Mol Endocrinol 1994 Aug
PMID:Evidence that signalling pathways by which thyrotropin-releasing hormone and gonadotropin-releasing hormone act are both common and distinct. 752 98

Inhibition of the growth of hormone related human tumor cells in vitro by GnRH agonists and antagonists suggests a direct effect on cell growth and proliferation, and this effect may be achieved through its receptors present in tumor cells. However, the nature of the GnRH receptors present in these tumors is controversial. To determine the molecular characteristics of GnRH receptors in such tumors, we used the reverse transcriptase/polymerase chain reaction (RT/PCR) technique to clone these receptors. Primers were selected from the human pituitary GnRH receptor cDNA sequence to amplify the open reading frame and parts of its 5' and 3'-untranslated sequences. Nucleotide sequencing of the GnRH receptor cDNAs from a breast tumor cell line (MCF-7) and from an ovarian tumor showed identity with that of the human pituitary GnRH receptor which binds GnRH with high affinity. GnRH receptor mRNA was found to be expressed in human pituitary, breast, breast tumor, ovary, ovarian tumor, prostate, prostate tumor and in breast tumor cell lines (MCF-7 and MDA-MB 468) and prostate tumor cell lines (PC-3 and LNCaP). These findings demonstrate that a mRNA representing the pituitary form of the GnRH receptor (which shows high affinity binding with GnRH) is also expressed in certain normal tissues and in hormone related human tumors and tumor cell lines derived from them.
Mol Cell Endocrinol 1994 Dec
PMID:The nucleotide sequences of human GnRH receptors in breast and ovarian tumors are identical with that found in pituitary. 753 32

1. The cloning of the mammalian gonadotropin-releasing hormone receptor sets the stage for rapid progress in understanding the structure of the receptor, its interaction with ligand, and its mechanisms of activation. 2. The receptor is a 327 to 328-amino acid seven-transmembrane domain G protein-coupled receptor. 3. Recent site-direct mutagenesis studies have provided considerable insight into glycosylation of the receptor, the arrangement of the helices, and the ligand binding domains.
Cell Mol Neurobiol 1995 Feb
PMID:Functional domains of the gonadotropin-releasing hormone receptor. 764 8

The interaction of gonadotropin-releasing hormone and its receptor is a critical event in the endocrine regulation of reproduction. We have recently cloned the gene encoding for the human gonadotropin-releasing hormone receptor (hGnRHR). Partial sequence analysis revealed a structural organization consisting of three exons and two introns. Exon II contains only 219 bp and the remainder of the approximately 5 kb transcript is distributed between exons I and III. The complete coding region for the hGnRHR represented only 987 bp leaving an extensive 5' and 3' non-translated region and potentially additional exons unaccounted for. This report provides the complete sequence of exon I and III and demonstrates that further exons are unlikely to be contained within this gene. Sequencing of the 5' end of the gene revealed the presence of five consensus TATA sequences distributed within a 700 nucleotide region. Primer extension analysis detected multiple transcription initiation sites associated with this cluster of TATA sequences. Transcription of this region up to the most 5' initiation site was demonstrated by the reverse transcription-polymerase chain reaction (RT-PCR) method. The 5' non-translated region stretches between 703 and 1393 bp, depending on which initiation site is used. Several consensus cis-acting regulatory sequences were identified within the 5' end. These include, among others, sites for PEA-3, AP-1, and Pit-1. In addition, cAMP response element (CRE)-like and glucocorticoid/progesterone response element (GRE/PRE)-like sequences were found.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1995 Feb
PMID:The human gonadotropin-releasing hormone receptor gene: complete structure including multiple promoters, transcription initiation sites, and polyadenylation signals. 776 23

The asparagine residues of the three N-glycosylation consensus sequences in the mouse gonadotropin-releasing hormone receptor were mutated to determine which residues were glycosylated and the function of glycosylation. Photoaffinity labelled Gln4 and Gln18 receptor mutants exhibited lower apparent molecular weight on SDS polyacrylamide gel electrophoresis, while the Gln102 receptor showed wildtype mobility. This indicates that the receptor is glycosylated at Asn4 and Asn18 but not at Asn102. Binding affinities of all the mutant receptors were normal, indicating that carbohydrate moieties are not involved in ligand binding interactions. However, expression of the Gln4 and Gln18 receptors were substantially decreased, indicating a role for glycosylation in receptor expression or stability. All the glycosylation site mutants were capable of normal signal transduction, as indicated by their ability to stimulate inositol phosphate production.
Mol Cell Endocrinol 1995 Feb
PMID:Identification of N-glycosylation sites in the gonadotropin-releasing hormone receptor: role in receptor expression but not ligand binding. 776 36

The cDNA encoding the gonadotropin-releasing hormone (GnRH) receptor has recently been cloned and characterized in several species, including human. To determine the structure of the gene encoding the human GnRH receptor, we have screened a human genomic library and isolated seven positive clones, using cDNA probes derived from a human pituitary cDNA library. The isolated genomic clone contains the entire protein coding region of the GnRH receptor which is distributed between three exons and spans over 18.9 kb. Sequence analysis and restriction endonuclease mapping revealed the presence of two introns of 4.2 and 5.0 kb, respectively, both located within the open reading frame, designating the human GnRH receptor gene to the intron-containing class of the G-protein coupled receptor superfamily. Genomic Southern blot analysis indicated the presence of a single copy of the gene encoding for the GnRH receptor within the human genome. Using DNA from human-hamster somatic hybrid cell lines, the GnRH receptor gene was assigned to human chromosome 4, by means of PCR. The present study represents the first report on the GnRH receptor gene and its partial characterization should facilitate further investigation of the mechanisms by which expression of this gene is regulated.
Mol Cell Endocrinol 1994 Jul
PMID:The human gonadotropin-releasing hormone (GnRH) receptor gene: cloning, genomic organization and chromosomal assignment. 795 84

Signal amplification is fundamental to the normal operation of the preovulatory LH surge and is achieved through processes such as GnRH self-priming and augmentation of stimulated LH secretion by progesterone. We have proposed a model for GnRH self-priming that requires cross-communication between a GnRH receptor-activated protein kinase A pathway and the progesterone receptor (PR) to achieve amplification of the GnRH signal. We found that a pulse of GnRH administered to gonadotrope-enriched pituitary cells cultured in medium containing charcoal-treated serum plus estradiol (E2) potentiated the LH secretory response to subsequent GnRH pulses, and this potentiation could be blocked by a PR antagonist, RU486, in the absence of progesterone. Similarly, exposure of gonadotrope-enriched cultures to forskolin augmented the response to a pulse of GnRH, and the augmentation due to cAMP elevation could be reduced by RU486 in the absence of progesterone. To directly test whether stimulation with either GnRH or a cAMP analog results in transactivation of the endogenous PR, we used rat anterior pituitary cells cultured in the presence of E2 and transfected with reporter plasmids containing progesterone-responsive elements (PRE) and either a E1b or a thymidine kinase (tk) promoter linked to the chloramphenicol acetyltransferase (CAT) gene. For pituitary cells transfected with the PRE-E1b-CAT plasmid, exposure to either progesterone, GnRH, or 8-bromo-cAMP (8BrcAMP) for 6 h resulted in an induction of CAT activity which could be suppressed by coincubation with RU486. RU486 by itself had no effect on CAT activity. Similar results were obtained when a plasmid containing a different promoter (PRE-tk-CAT) was used. For cells transfected with a construct lacking a PRE (pSV2CAT), 8BrcAMP was without effect on CAT expression. When cells were made PR-deficient by omission of E2 from the incubation medium and transfected with PRE-E1b-CAT, neither progesterone, GnRH, nor 8BrcAMP was able to induce CAT activity. In summary we found that either GnRH or 8BrcAMP is able to stimulate transcription of reporter genes linked to two different PRE-containing promoters in anterior pituitary cells that contain endogenous PR; this occurred in the absence of progesterone and was suppressed by a PR antagonist. A simple interpretation of these data is that a GnRH-triggered signaling cascade can result in progesterone-independent transactivation of the PR. We propose that, in the normal operation of the preovulatory LH surge, the pathways for GnRH self-priming and progesterone augmentation converge at the PR and that the pathways serve as physiological redundancies to ensure the LH surge.
Mol Endocrinol 1994 Jul
PMID:Activation of the progesterone receptor by the gonadotropin-releasing hormone self-priming signaling pathway. 798 48

The alpha T3-1 cell line, an immortalized gonadotroph cell line, expresses high levels of the gonadotrophin-releasing hormone (GnRH) receptor. Sustained exposure of these cells to the GnRH receptor agonist des-Gly10-[D-Ala6]luteinizing hormone-releasing hormone ethylamide resulted in a substantial down-regulation of cellular levels of a combination of the alpha subunits of the phospholipase C-beta 1-linked G proteins Gq and G11, as assessed by immunoblotting with an antiserum able to identify these two proteins equally. This effect was dependent upon the concentration of agonist used (EC50 = 4 nM) and on the time of the treatment (t1/2 = 6 hr) when a maximally effective concentration of agonist (1 microM) was used. Comparison of agonist regulation of inositol phosphate generation and Gq alpha/G11 alpha down-regulation demonstrated that effects on inositol phosphate production were approximately 3-fold more potent. In contrast to Gq alpha/G11 alpha, membrane-associated levels of Gs alpha and G12 alpha, the G proteins that transduce stimulatory and inhibitory regulation, respectively, of adenylyl cyclase, were not altered by agonist treatment. Analysis of mRNA by reverse transcriptase/polymerase chain reaction indicated the coexpression by alpha T3-1 cells of mRNA corresponding to both Gq alpha and G11 alpha. Immunoblotting with antisera selective for either Gq alpha or G11 alpha confirmed their coexpression. Resolution of membranes from untreated and agonist-treated alpha T3-1 cells under sodium dodecyl sulfate-polyacrylamide gel electrophoresis conditions able to separate Gq alpha from G11 alpha indicated that G11 alpha was more prevalent than Gq alpha at steady state but that agonist treatment regulated cellular levels of both of these G proteins in a nonselective manner. Sustained activation of protein kinase C with phorbol myristate acetate was unable to mimic agonist regulation of cellular Gq alpha/G11 alpha levels, as was treatment of alpha T3-1 cells with the selective protein kinase C inhibitor chelerythrine. These data suggest that the GnRH receptor is able to interact functionally with both Gq alpha and G11 alpha in alpha T3-1 cells and that sustained exposure to a GnRH receptor agonist selectively regulates the cellular levels of the G proteins that interact with the receptor.
Mol Pharmacol 1994 Jul
PMID:The gonadotrophin-releasing hormone receptor of alpha T3-1 pituitary cells regulates cellular levels of both of the phosphoinositidase C-linked G proteins, Gq alpha and G11 alpha, equally. 805 44


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