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)

Enhanced secretion of PGF2 alpha from endometrial explants in vitro in response to oxytocin is associated with augmented activities of phospholipase A2, phospholipase C and prostaglandin endoperoxide H synthase (PGS). In early pregnancy, maintenance of the corpus luteum is associated with an absence of pulsatile PGF2 alpha secretion; an increase in endometrial inhibitors of phospholipase A2 and PGS contribute to the antiluteolytic alterations of PGF2 alpha secretion. Linoleic acid is a competitive inhibitor of arachidonic acid metabolism by PGS, and microsomal concentrations of free linoleic acid are increased in the endometrium of pregnant cattle. The trophoblast produces large quantities of interferon tau (IFN-tau). Inhibition of increases in endometrial oestradiol receptor mRNA and protein are associated with intrauterine administration of recombinant (r) ovine (o) IFN-tau in sheep. Intrauterine injections of ovine (b) IFN-tau in cattle (days 14-17) altered endometrial function so that secretion of PGF2 alpha from cultured endometrial epithelial cells was reduced. Antiluteolytic effects were not expressed in 20% of cows receiving IFN-tau or rbIFN-alpha I1 indicating that an inadequate endometrial responsiveness may contribute to embryo mortality. IFN-tau may activate a signal transduction system similar to that induced by other type I IFNs; activation of an intracellular tyrosine kinase ultimately leads to activation of an IFN-stimulated response element to induce gene transcription. Biological responses associated with pregnancy and IFN-tau treatment are integrated into a multifactorial antiluteolytic model. Strategies to enhance embryo survival could include supplementation with rIFN-tau and alterations in endometrial responsiveness to this cytokine through dietary manipulation of lipid metabolism.
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PMID:Maternal recognition of pregnancy. 762 10

The present experiments were designed to investigate the mechanisms involved in the contractile responses evoked by KCl, added either isoosmotically or hyperosmotically, in the rat uterus. Exposure of uterine strips to a Ca(2+)-free, 3 mM EGTA-containing solution abolished the responses induced by isoosmotic KCl solutions. Conversely, addition of hyperosmolar KCl induced concentration-dependent tonic responses in a Ca(2+)-free, 3 mM EGTA-containing solution. The maximum increase in tension was reached with 210 mM K+. The response to hyperosmotic K+ was unaffected by previous depletion of intracellular Ca2+ stores with oxytocin (1 microM), by inhibition of refilling of the intracellular Ca2+ stores using cyclopiazonic acid (10 microM) or by increasing the concentration of EGTA in the medium to 10 mM. Sucrose and mannitol (60-420 mM) induced concentration-dependent sustained contractions which were not reproducible and were significantly smaller in size than those evoked by the maximally effective concentration of hyperosmotic K+ (210 mM). The contraction induced by hyperosmotic K+ in Ca(2+)-free solution was not altered by the calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7, 100 microM), the Ca2+/calmodulin protein kinase II inhibitor 1-[N,O-bis(1,5-isoquinolinesulphonyl)-N-methyl-L-tyrosyl]-4-phenyl piperazine (KN-62, 10 microM) or the tyrosine kinase inhibitor genistein (10 microM). The protein kinase C inhibitor calphostin C (1-3 microM) failed to modify the K(+)-effect curve, which was however partially inhibited in the presence of the non-selective protein kinase inhibitor 1-(5-isoquinolinylsulphonyl)-2 methylpiperazine dihydrochloride (H-7, 3-100 microM). The protein kinase inhibitor staurosporine (30-300 nM) depressed the contraction induced by hyperosmolar K+ in a concentration-dependent manner. The contraction induced by sucrose in Ca(2+)-free solution was unaffected by W-7 (100 microM) and KN-62 (10 microM) but was partially reduced by calphostin C (1 microM), H-7 (30 microM), staurosporine (100 nM) and genistein (10 microM). These results suggest that different mechanisms are involved in the responses evoked by isoosmotic and hyperosmotic KCl in the rat uterus. A component of the contraction induced by hypertonic KCl seems mainly independent of both external and internal Ca2+ and of hyperosmolar stress. This contraction is not mediated by protein kinase C, Ca2+/calmodulin-dependent kinases or protein tyrosine kinases but involves activation of other, at the present unknown, staurosporine-sensitive protein kinase(s).
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PMID:Ca(2+)-independent contraction induced by hyperosmolar K(+)-rich solutions in rat uterus. 889 13

Intracellular mediators regulating the initiation of parturition are not fully understood. This study was designed to determine the possible mechanism of oxytocin-induced uterine contractility during labour. In-vitro isometric contraction studies were performed with longitudinal strips of human pregnant myometrium in the presence and absence of the protein kinase C inhibitors, staurosporine and RO 31-8220, and the tyrosine kinase inhibitor, genistein. Phospholipase D activity was measured by employing the transphosphatidylation reaction. Staurosporine significantly reduced oxytocin-stimulated contractile activity with mean activity reduced by > 50% following the addition of 10(-6) M staurosporine (P < 0.01), while addition of 10(-5) M resulted in a measured mean contractile activity of approximately 10% of the control (P < 0.001, n = 5). Similarly, uterine activity was minimal with oxytocin application following incubation with RO 31-8220, mean contractile activity being reduced by approximately 40% by the addition of 10(-7) M RO 31-8220 (P < 0.05) and by approximately 87% by the addition of either 10(-6) or 10(-5) M (P < 0.01, n = 3). Conversely, addition of genistein (10(-7) and 10(-6) M) had little effect on oxytocin-induced contractions, although at a higher concentration (10(-5) M) a significant reduction in oxytocin-induced contractile activity was observed (P < 0.01). Oxytocin evoked phospholipase D activation in a concentration- and time-dependent manner in cultured human pregnant myometrial cells (n = 4). These results indicate that activation of protein kinase C and tyrosine kinase are involved in the regulation of oxytocin-mediated myometrial contractile activity and that a coupled phospholipase D/phosphatidate phosphohydrolase pathway may play a role in the sustained stimulation of myometrial activity during labour.
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PMID:Activation of protein kinase C is required for oxytocin-induced contractility in human pregnant myometrium. 894 42

The objective of this study was to investigate the mechanism of action of PGF2 alpha in cultured human myometrial cells. We measured the effects of PGF2 alpha and fluprostenol, a selective PGF2 alpha receptor (FP receptor) agonist, on phospholipase C(PLC) activation, on changes in the intracellular free calcium concentration ([Ca2+]i), and on protein tyrosine phosphorylation. PGF2 alpha and fluprostenol activated PLC (determined by measuring the formation of inositol phosphates) and increased [Ca2+]i in a concentration-dependent manner. The apparent affinity of the FP receptor for fluprostenol was higher than that for PGF2 alpha when measuring PLC activation, but the receptor displayed similar affinities for both agonists when measuring increases in [Ca2+]i. These effects were not altered by treating the cells with pertussis toxin (PT), suggesting that the FP receptor is linked to PLC activation by a G protein of the Gq family. By contrast, the effect of oxytocin on PLC activation involved both PT-resistant and PT-sensitive pathways. Human myometrial cells responded to pervanadate and epidermal growth factor with increased PLC activity and increased tyrosine phosphorylation, demonstrating a functional PLC-gamma tyrosine kinase pathway. However, neither fluprostenol nor oxytocin stimulated tyrosine phosphorylation, but the effects of both agonists were inhibited after protein kinase C stimulation. These data suggest that fluprostenol and oxytocin activate PLC-beta rather than PLC-gamma isoforms. The effect of fluprostenol is Ca2+ dependent, but is unlikely to involve a direct effect of Ca2+ on PLC activity.
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PMID:Fluprostenol activates phospholipase C and Ca2+ mobilization in human myometrial cells. 896 35

As the oxytocin receptor plays a key role in parturition and lactation, there is considerable interest in defining its structure/functional relationships. We previously showed that the rat oxytocin receptor transfected into Chinese hamster ovary cells was coupled to both G(q/11) and G(i/o), and that oxytocin stimulated ERK-2 phosphorylation and prostaglandin E(2) synthesis via protein kinase C activity. In this study, we show that deletion of 51 amino acid residues from the carboxyl terminus resulted in reduced affinity for oxytocin and a corresponding rightward shift in the dose-response curve for oxytocin-stimulated [Ca(2+)](i). However, oxytocin-stimulated ERK-2 phosphorylation and prostaglandin E(2) synthesis did not occur in cells expressing the truncated receptor. Oxytocin also failed to increase phospholipase A activity or activate protein kinase C, indicating that the mutant receptor is uncoupled from G(q)-mediated pathways. The Delta51 receptor is coupled to G(i), as oxytocin-stimulated Ca(2+) transients were inhibited by pertussis toxin, and a Gbetagamma sequestrant. Preincubation of Delta51 cells with the tyrosine kinase inhibitor, genistein, also blocked the oxytocin effect. A Delta39 mutant had all the activities of the wild type oxytocin receptor. These results show that the portion between 39 and 51 residues from the COOH terminus of the rat oxytocin receptor is required for interaction with G(q/11), but not G(i/o). Furthermore, an increase in intracellular calcium was generated via a G(i)betagamma-tyrosine kinase pathway from intracellular stores that are distinct from G(q)-mediated inositol trisphosphate-regulated stores.
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PMID:The proximal portion of the COOH terminus of the oxytocin receptor is required for coupling to g(q), but not g(i). Independent mechanisms for elevating intracellular calcium concentrations from intracellular stores. 1049 38

These studies sought to test the hypothesis that tyrosine kinase-stimulated phasic myometrial contractions are mediated by activation of the phosphatidylinositol (PI)-signaling pathway and the generation of cytosolic calcium oscillations. For these studies, uterine tissue was obtained from adult female Sprague-Dawley white rats during the proestrus/estrus phase of the cycle. In vitro contraction studies were performed using pervanadate (a tyrosine phosphatase inhibitor) with and without inhibitors of the PI-signaling pathway, including 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (a phospholipase C inhibitor), thimerosal (an inositol-trisphosphate receptor/channel inhibitor), and Ruthenium red (a ryanodine receptor inhibitor), and with oxytocin or prostaglandin F2 alpha (two classic uterotonic agonists). Cytosolic calcium studies were performed using Fura-2-loaded myometrial strips. During these studies, pervanadate was observed to produce cytosolic calcium oscillations and phasic contractions in myometrial tissue comparable to those produced in response to oxytocin and prostaglandin F2 alpha. The pervanadate-stimulated phasic contractions were significantly suppressed in response to inhibition of phospholipase C, the inositol-trisphosphate receptor, and the ryanodine receptor, thereby confirming the importance of the PI-signaling pathway during tyrosine kinase-associated myometrial activity. Further confirming the important and shared role for the PI-signaling pathway during pervanadate-stimulated myometrial contractions, no significant additive effects were observed when classic uterotonic agonists such as oxytocin or prostaglandin F2 alpha were combined with pervanadate.
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PMID:Tyrosine kinase-mediated activation of cytosolic calcium oscillations and phasic myometrial contractions. 1055 61

Despite oxytocin receptors (OTR) being present in human chorio-decidual tissues, their expression and role in placental trophoblast cells in the context of tumor growth or physiological functions related to cell proliferation have never been examined. In the present study we demonstrate the presence and functionality of OTR in normal human trophoblast cell lines (ED77 and ED27) and a choriocarcinoma cell line (BeWo). RT-PCR and immunofluorescence analysis revealed the presence of OTR messenger RNA and protein in these cells. Binding studies using [(125)I]oxytocin ([(125)I]OT) antagonist confirmed the presence of specific binding sites in ED27, ED77, and BeWo cells. OTR functionality was demonstrated by measuring the OT-induced increase in the intracellular calcium concentrations. This effect was dose dependent and was blocked by the selective OT antagonist d(CH(2))(5)[Tyr(Me)(2),Thr(4), Tyr-NH(2)(9)]OVT (OT antagonist). Furthermore, two proteins with apparent molecular masses of 125 and 60 kDa became tyrosine phosphorylated in all of the cell lines after OT stimulation (and an additional protein of 45 kDa in BeWo choriocarcinoma cells), suggesting that this peptide can stimulate tyrosine kinase activity. Finally, we observed a dose-dependent OT stimulation of cell proliferation associated with OTR activation that was completely abolished by the selective OT antagonist. These findings provide the first evidence of the presence of functional OTR in normal trophoblast cell lines as well as in choriocarcinoma cells and show that a specific effect of OT on normal and neoplastic trophoblast is to promote cellular proliferation.
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PMID:Activation of functional oxytocin receptors stimulates cell proliferation in human trophoblast and choriocarcinoma cell lines. 1118 28

Regulators of G protein signaling (RGS proteins) interact with Galpha(q) and Galpha(i) and accelerate GTPase activity. These proteins have been characterized only within the past few years, so our understanding of their importance is still preliminary. We examined the effect of oxytocin on RGS2 mRNA expression to help determine the role of RGS proteins in oxytocin signaling in human myometrial cells in primary culture. Oxytocin increased RGS2 mRNA concentration maximally by 1 or 2 h in a dose-dependent and agonist-specific manner. RGS2 mRNA levels were also elevated by treatment with Ca(2+) ionophore, phorbol ester, or forskolin. Oxytocin's effects were completely inhibited by an intracellular Ca(2+) chelator and partially blocked by a protein kinase C inhibitor, indicating that intracellular Ca(2+) concentration is the primary signal for oxytocin elevation of RGS2 mRNA levels. Use of pharmacological inhibitors indicated that part of oxytocin-stimulated RGS2 mRNA expression is mediated by G(i)/tyrosine kinase activities. Although oxytocin does not stimulate increases in intracellular cAMP concentration, agents that elevate intracellular cAMP concentrations and cause myometrial relaxation may possibly cause heterologous desensitization to oxytocin via RGS2 expression. These results suggest that RGS2 may be important in regulating the myometrial response to oxytocin.
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PMID:Oxytocin stimulation of RGS2 mRNA expression in cultured human myometrial cells. 1183 60

MAP (mitogen-activated protein) kinase (also called Erk 1/2) plays a crucial role in cell proliferation and differentiation. Its impact on secretory events is less well established. The interplay of protein kinase C (PKC), PI3-kinase and cellular tyrosine kinase with MAP kinase activity using inhibitors and compounds such as glucose, phorbol 12-myristate 13-acetate (PMA) and agonists of G-protein coupled receptors like gastrin releasing peptide (GRP), oxytocin (OT) and glucose-dependent insulinotropic peptide (GIP) was investigated in INS-1 cells, an insulin secreting cell line. MAP kinase activity was determined by using a peptide derived from the EGF receptor as a MAP kinase substrate and [32P]ATP. Glucose as well as GRP, OT and GIP exhibited a time-dependent increase in MAP kinase activity with a maximum at time point 2.5 min. All further experiments were performed using 2.5 min incubations. The flavone PD 098059 is known to bind to the inactive forms of MEK1 (MAPK/ERK-Kinase) thus preventing activation by upstream activators. 20 microM PD 098059 (IC50 = 5 microM) inhibited MAP kinase stimulated by either glucose, GRP, OT, GIP or PMA. Inhibiton ("downregulation") of PKC by a long term (22 h) pretreatment with 1 microM PMA did not influence MAP kinase activity when augmented by either of the above mentioned compound. To investigate whether PI3-kinase and cellular tyrosine kinase are involved in G-protein mediated effects on MAP kinase, inhibitors were used: 100 nM wortmannin (PI3-kinase inhibitor) reduced the effects of GRP, OT and GIP but not that of PMA; 100 microM genistein (tyrosine kinase inhibitor) inhibited the stimulatory effect of either above mentioned compound on MAP kinase activation. Inhibition of MAP kinase by 20 microM PD 098059 did not influence insulin secretion modulated by either compound (glucose, GRP, OT or GIP). [3H]Thymidine incorporation, however, was severely inhibited by PD 098059. Thus MAP kinase is important for INS-1 cell proliferation but not for its insulin secretory response with respect to major initiators and modulators of insulin release. The data indicate that MAP kinase is active and under the control of MAP kinase. PKC is upstream of a genistein-sensitive tyrosine kinase and probably downstream of a PI3-kinase in INS-1 cells.
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PMID:Role of protein kinase C, PI3-kinase and tyrosine kinase in activation of MAP kinase by glucose and agonists of G-protein coupled receptors in INS-1 cells. 1236 12

The mechanisms by which oxytocin (OT) stimulates extracellular signal-regulated kinase 1/2 (ERK1/2) are only partially understood. OT receptor (OTR) signals predominantly through Galpha(q), but ERK1/2 phosphorylation (ERK1/2-P) in PHM1 myometrial cells was not eliminated by inhibition of downstream effectors such as phospholipase C or protein kinase C. Inconsistent with a Galpha(i)-coupled response, pertussis toxin inhibition of OT-induced ERK1/2-P was reversed by the protein kinase A inhibitors Rp-cAMPS and KT5720. Consistent with an inhibitory role for protein kinase A, pertussis toxin pretreatment raised cellular cAMP and 8-(4-chlorophenylthio)-cAMP inhibited OT-induced ERK1/2-P. Attenuation of the OT response by the Gbetagamma scavenger carboxyl terminus of the beta-adrenergic receptor kinase implicated a Gbetagamma-mediated pathway. In both COSM6 cells overexpressing OTR (OTR-COSM6) and in PHM1 cells, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478 markedly reduced OT-induced ERK1/2-P, whereas the platelet-derived growth factor receptor tyrosine kinase inhibitor AG1296 had no effect. Furthermore, OT increased EGFR tyrosine phosphorylation in OTR-COSM6 cells, which was inhibited by AG1478 or EGTA plus thapsigargin pretreatment. AG1478 did not affect inositol 1,4,5-triphosphate production by OT or protein kinase C-stimulated ERK1/2-P but completely blocked ionomycin-induced ERK1/2-P and EGFR tyrosine phosphorylation. In both OTR-COSM6 and PHM1 cells, EGTA reduced OT-stimulated ERK1/2-P; no ERK1/2-P was observed when intracellular calcium increases were blocked by pretreatment with thapsigargin plus EGTA. These data are consistent with activation of a Gbetagamma-mediated pathway as a consequence of Galpha(q) activation in myometrium and OTR-COSM6 cells that results in increased ERK1/2-P. This pathway involves both EGFR activation and an influence of calcium.
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PMID:Extracellular signal-regulated kinase 1/2 activation by myometrial oxytocin receptor involves Galpha(q)Gbetagamma and epidermal growth factor receptor tyrosine kinase activation. 1281 May 50


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