Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P01178 (oxytocin)
15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nonapeptide hormones arginine vasopressin (CYFQNCPRG-NH2, AVP) and oxytocin (CYIQNCPLG-NH2, OT), control many essential functions in mammals. Their main activities include the urine concentration (via stimulation of AVP V2 receptors, V2R, in the kidneys), blood pressure regulation (via stimulation of vascular V1a AVP receptors, V1aR), ACTH control (via stimulation of V1b receptors, V1bR, in the pituitary) and labor and lactation control (via stimulation of OT receptors, OTR, in the uterus and nipples, respectively). All four receptor subtypes belong to the GTP-binding (G) protein-coupled receptor (GPCR) family. This work consists of docking of YM087, a potent non-peptide V1aR and V2R - but not OTR - antagonist, into the receptor models based on relatively new theoretical templates of rhodopsin (RD) and opiate receptors, proposed by Mosberg et al. (Univ. of Michigan, Ann Arbor, USA). It is simultaneously demonstrated that this RD template satisfactorily compares with the first historical GPCR structure of bovine rhodopsin (Palczewski et al., 2000) and that homology-modeling of V2R, V1aR and OTR using opiate receptors as templates is rational, based on relatively high (20-60%) sequence homology among the set of 4 neurophyseal and 4 opiate receptors. YM087 was computer-docked to V1aR, V2R and OTR using the AutoDock (Olson et al., Scripps Research Institute, La Jolla, USA) and subsequently relaxed using restrained simulated annealing and molecular dynamics, as implemented in AMBER program (Kollman et al., University of California, San Francisco, USA). From about 80 diverse configurations, sampled for each of the three ligand/receptor systems, 3 best energy-relaxed complexes were selected for mutual comparisons. Similar docking modes were found for the YM087/V1aR and YM087/V2R complexes, diverse from those of the YM087/OTR complexes, in agreement with the molecular affinity data.
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PMID:Molecular modeling of interactions of the non-peptide antagonist YM087 with the human vasopressin V1a, V2 receptors and with oxytocin receptors. 1216 92

The function and physiological regulation of the oxytocin-receptor system is strongly steroid-dependent. This is, unexpectedly, only partially reflected by the promoter sequences in the oxytocin receptor and favors the idea that posttranscriptional mechanisms may also play a significant role for the physiological regulation of the oxytocin-receptor system. Our data indicate that cholesterol acts as an allosteric modulator of the oxytocin receptor and stabilizes both membrane-associated and solubilized OT receptors in a high-affinity state for agonists and antagonists. Moreover, high-affinity OT receptors are 2-fold enriched in cholesterol-rich plasma membrane domains in HEK293 fibroblasts stably expressing the human OT receptor. Biochemical data suggest a direct and cooperative molecular interaction of cholesterol molecules with OT receptors. To localize the cholesterol interacting domain of the oxytocin receptor the C-terminal part including the last two transmembrane domains have been exchanged by the corresponding sequences of the cholecystokinin type B receptor, which is functionally not dependent on cholesterol. Concerning its ligand-binding behavior this chimeric receptor protein showed the same dependence on cholesterol and its analogues as the wild type oxytocin receptor. From mutagenesis experiments and studies with receptor chimera between the OTR and cholecystokinin type B receptor, we conclude that a major part of the cholesterol interacting domain may be localized in the first part of the oxytocin receptor, possibly in a domain nearby the agonist binding site. Progesterone is considered to be essential to maintain the uterine quiescence. High concentrations of progesterone (> 10 microM) attenuate or block the signaling of several GPCRs, including the OT receptor via a fast, reversible and non-genomic pathway. Progesterone is known to inhibit both cholesterol biosynthesis and the intracellular trafficking of cholesterol. We therefore test the hypothesis that progesterone affects the signal transduction and subdomain localization of receptors via its influence on cholesterol trafficking. Since cholesterol-rich subdomains (rafts) are considered to be organization centers for cellular signal transduction, changes of the level or distribution of cholesterol may have profound effects on receptor-mediated signaling in general. Using fluorescence recovery after photobleaching (FRAP) measurements with GFP-tagged oxytocin receptors the influence of steroids on the mobility and distribution of the oxytocin receptor in the plasma membrane was analyzed. Progesterone had no effect on the lateral mobility of the oxytocin receptor, but it led to marked inhibition of cellular motility such as vesicle trafficking and movements of filopodia. Non-genomic effects of progesterone and estradiol with respect to receptor signaling as well as the influence of cholesterol on signal transduction will be discussed in more detail.
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PMID:Cholesterol and steroid hormones: modulators of oxytocin receptor function. 1243 25

We have recently shown that oxytocin inhibits cell proliferation when the vast majority of oxytocin receptors are excluded from caveolin-1-enriched microdomains, and that, on the contrary, it has a mitogenic effect when the receptors are targeted to these plasma membrane domains. In this study, we investigated whether the receptors located inside and outside caveolar microdomains initiate different signalling pathways and how this may lead to opposite effects on cell proliferation. Our data indicate that, depending on their localization, oxytocin receptors transactivate EGFR and activate ERK1/2 using different signalling intermediates. The final outcome is a different temporal pattern of EGFR and ERK1/2 phosphorylation, which is more persistent when the receptors are located outside caveolar microdomains and inhibit cell growth, and very transient when they are located in caveolar microdomains and stimulate cell growth. Finally, only the activation of receptors located outside caveolar microdomains correlates with the activation of the cell cycle inhibitor p21(WAF1/CIP1), thus suggesting that the antiproliferative OTR effects may, in this case, be achieved by a sustained activation of EGFR and MAPK leading to the induction of this cell cycle regulator.
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PMID:Oxytocin receptor elicits different EGFR/MAPK activation patterns depending on its localization in caveolin-1 enriched domains. 1295 84

Estradiol (E2), progesterone (P4), and oxytocin (OT) are important for the initiation of luteolysis in ruminants but the mechanisms involved are still poorly understood. The objective of this study was to determine if duration of exposure of bovine endometrial epithelial cells to P4 affected the response of the cells to E2. Endometrial epithelial cells, from cows at Days 1-3 of the estrous cycle, were cultured for 10, 17, and 21 days in the presence or absence of P4 (100 ng ml(-1)). After culture, each group of cells was incubated for a further 6, 12, 24 or 48 h with or without E2 (100 pg ml(-1)) and then incubated for 6 h with different doses of OT (2, 20, and 200 ng ml(-1)). E2 enhanced OT-stimulated PGF2 alpha secretion in cells cultured with P4 for 17 or 21 days, with a maximum effect after 24-h exposure, but not in cells cultured with P4 for 10 days. To determine the mechanism of action of E2, COX-1 and COX-2 were measured by Western blotting and OTR number was measured by saturation analysis. OT increased COX-2 (P<0.05), but there was no significant effect of E2 on the expression of either COX-1 or COX-2. E2 did, however, increase (P<0.001) the OTR number in cells cultured with P4 for 21 days, whereas it inhibited OTR in cells cultured for 10 days. These data show that E2 can stimulate PGF2 alpha secretion by increasing OTR expression in bovine endometrial cells in vitro, but only after exposure to P4.
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PMID:Prolonged progesterone treatment of endometrial epithelial cells modifies the effect of estradiol on their sensitivity to oxytocin. 1295 70

Since 30 years the rate of preterm deliveries of 7% remained unchanged. This is due to a lack of understanding of the underlying pathomechanisms of preterm labor. Oxytocin (OT) as well as its receptor (OTR) play a key role in the process of (preterm) labor as part of a paracrine system that regulates myometrial contractility. Binding of OT to its corresponding receptor, OTR, leads to activation of actin-myosin interactions and therewith myometrial contractions as well as production of intrauterine prostaglandins (PGE(2), PGF(2 alpha)) mainly in decidua and myometrium. Oxytocin expression increases significantly at time of parturition, as does the expression of its receptor. Both can be influenced by diverse cellular substrates. The focus of our research group is based on the exploration of the influence of cytokines on OTR signaling.
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PMID:[The oxytocin signal cascade during premature labor]. 1455 93

We report the solid phase synthesis and some pharmacological properties of seventeen new oxytocin (OT) analogues. Basic modification at positions 8 and/or 9 (introduction of L-alpha-t-butylglycine [Gly(Bu(t))]) was combined with D-Cys(6), D-Tyr(Et)(2), Mpa(1) or Pen(1) modifications and their various combinations. We also present properties of two previously reported re-synthesized analogues ([Gly(Bu(t))(8)]OT and [Mpa(1), Gly(Bu(t))(8)]OT). The analogues were tested for rat uterotonic activity in vitro, in the rat pressor assay and for binding affinity to human OTR.
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PMID:Synthesis and biological evaluation of oxytocin analogues containing L-alpha-t-butylglycine [Gly(Bu t)] in positions 8 or 9. 1470 58

Neurohypophysial oxytocin (OT) and vasopressin (VP) genes are transcribed in thymic epithelium, while immature T lymphocytes express functional neurohypophysial receptors. Neurohypophysial receptors belong to the G protein-linked seven-transmembrane receptor superfamily and are encoded by four distinct genes, OTR, V1R, V2R and V3R. The objective of this study was to identify the nature of neurohypophysial receptor in thymic T cell subsets purified by immunomagnetic selection, as well as in murine thymic lymphoma cell lines RL12-NP and BW5147. OTR is transcribed in all thymic T cell subsets and T cell lines, while V3R transcription is restricted to CD4+CD8+ and CD8+ thymic cells. Neither V1R nor V2R transcripts are detected in any kind of T cells. The OTR protein was identified by immunocytochemistry on thymocytes freshly isolated from C57BL/6 mice. In murine fetal thymic organ cultures, a specific OTR antagonist does not modify the percentage of T cell subsets, but increases late T cell apoptosis further evidencing the involvement of OT/OTR signaling in the control of T cell proliferation and survival. According to these data, OTR and V3R are differentially expressed during T cell ontogeny. Moreover, the restriction of OTR transcription to T cell lines derived from thymic lymphomas may be important in the context of T cell leukemia pathogenesis and treatment.
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PMID:Neurohypophysial receptor gene expression by thymic T cell subsets and thymic T cell lymphoma cell lines. 1515 11

The objective of this study was to disclose an interaction between Beta(2)-adrenergic (Beta(2)-ARs) and oxytocin (OT) receptors (OTRs) in the late-pregnant rat uterus. We investigated the level of uterine OTR mRNA expression after the administration of Beta(2)-AR agonists fenoterol and hexoprenaline to rats from day 18 to 22 of pregnancy, and also tested the effect of fenoterol on uterine explants. Hexoprenaline induced a maximum 24% increase of OTR mRNA. Fenoterol in vivo elicited a maximum 125% increase of OTR mRNA, in vitro produced a maximum fourfold increase in OTR mRNA. In fenoterol-treated rats the maximal contractility increasing effect of OT on isolated uterine rings was significantly higher than in intact term pregnant rats, but the EC50 values were not statistically different. It was concluded that the enhanced expression of OTR mRNA induced by Beta(2)-agonists in the late-pregnant rat uterus may be a possible drawback to effective therapy of preterm uterine contractions with Beta(2)-agonists.
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PMID:Beta 2-agonist treatment enhances uterine oxytocin receptor mRNA expression in pregnant rats. 1527 5

Ontogenesis of oxytocin (OT) and vasopressin (VP) gene expression and function were investigated in murine thymus. OT and VP transcripts were detected in the thymus on embryonic days 13 and 15, respectively. Corresponding messenger RNAs were evidenced in thymic epithelial cells by in situ hybridization with a neurophysin probe. From all OT and VP receptors, only OTR was expressed by all T-cell subsets, while V1bR was found in double positive and single positive CD8 cells. In fetal thymic organ cultures, OTR antagonist d[D-Tyr(Et)2, Thr4]OVT increased early apoptosis of CD8 cells, while V1bR antagonist (Sanofi SSR149415) inhibited T-cell differentiation, and favored CD8 T-cell commitment.
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PMID:Ontogenesis and functional aspects of oxytocin and vasopressin gene expression in the thymus network. 1558 39

Malignant growth of small-cell lung carcinoma is promoted by various neuroendocrine autocrine/paracrine loops. Therefore, to interfere with this mitogenic process, it is crucial to elucidate the mechanisms involved. It is known that the oxytocin (OT) and vasopressin (VP) genes, normally transcriptionally restricted in their expression, are activated in small-cell lung cancer (SCLC), concomitantly with expression of their receptors (OTR, V1aR, V1bR/V3R and V2R). The aim of the present study was to characterize, in concentrations close to physiological and pharmacological conditions, intracellular signalling events triggered by OT and VP binding to their specific receptors in SCLC cells and to identify factors mediating OT- and VP-induced mitogenic effects on SCLC. Known agonists for OTR ([Thr4,Gly7]OT) and V1aR (F180), in addition to OT and VP, were able to elicit increases in cytosolic Ca2+ levels and this effect could be blocked using an OTR antagonist (OVTA) or a V1aR antagonist (SR49059) respectively. There was no activation of the cAMP pathway detected after VP, dDAVP (a V2R agonist), or OT treatment. Stimulation of SCLC cells with OT and VP led to an increase of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, maximal at 5 min, and the subsequent phosphorylation of its downstream target p90 ribosomal S6 kinase (p90RSK). Pre-incubation with OVTA and SR49059, and with inhibitors of phospholipase C (PLC), protein kinase C (PKC), mitogen-activated protein kinase/ERK kinase (MEK) 1/2 and a Ca2+ chelator significantly reduced OT- and VP-induced ERK1/2 phosphorylations. OVTA, SR49059 as well as MEK1/2 and PKC inhibitors also downregulated OT- and VP-induced p90RSK phosphorylation. In [3H]thymidine-uptake experiments, we subsequently observed that PLC, Ca2+, PKC and ERK1/2 are absolutely required for the OT- and VP-stimulated SCLC cellular growth process. In conclusion, the results presented here indicate that OT- and VP-induced mitogenic effects on SCLC are respectively mediated by OTR and V1aR signalling and that this mitogenic signalling passes through the phosphorylation of ERK1/2 and p90RSK in a PLC-, Ca2+-, PKC- and MEK1/2-dependent pathway.
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PMID:Oxytocin- and vasopressin-induced growth of human small-cell lung cancer is mediated by the mitogen-activated protein kinase pathway. 1561 60


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