UNIPROT:P01178 - FACTA Search

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

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

Oxytocin (OT) inhibits the uptake of serotonin (5HT) into uterine mast cells. This may modulate 5HT bioavailability in the myometrium. Because 5HT isan important endogenous uterotonic compound, it has been postulated that this effect of OT may contribute to its potency as a labor inducer. This also predicts the presence of oxytocin receptors (OTRs) and transducing signals that will interact with 5HT transporters (SERT) in mast cells. In this study, OTR and SERT were characterized in murine peritoneal mast cells by radioligand-binding studies. Saturation assays for OTR showed no changes in Kd along the estrous cycle (6.95 +/- 2.76 nM in estrus and 4.07 +/- 1.73 nM in diestrus) but an increase in Bmax in estrus (0.71 +/- 0.08 pmol/10(6) cells and 0.37 +/- 0.05 pmol/10(6) cells in estrus and diestrus, respectively). Bmax and Kd for SERT were not affected along the estrous cycle. The signaling between the OTR and the SERT was analyzed by measuring the extent of inhibition of OT and PMA (activator of protein kinase C on 5HT uptake and the capability of Ro318220 (specific inhibitor of PKC) to increase 5HT uptake and block the effect of the above compounds in mast cells. The results showed that in murine peritoneal mast cells in vitro (1) ovarian hormones modulate OTR but not SERT expression, (2) the magnitude of OT action on 5HT uptake depends on the number of OTRs expressed in mast cells, and (3) the signaling between OTR and the SERT is mediated through the activation of protein kinase C. It is concluded that the ovarian hormones have a modulatory action on 5HT uptake which involves OT-mediated mechanism.
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PMID:Characterization of oxytocin receptors and serotonin transporters in mast cells. 1237 64

The modulatory effect of oxytocin (OT) on ATP-activated currents (I(ATP)) was studied in freshly isolated dorsal root ganglion (DRG) neurons of rats using whole cell clamp technique. In most of the neurons examined (50/70, 71.4%) extracellular application of OT (10(-9)-10(-5) mol/L) suppressed I(ATP) while in the rest (20/70, 28.6%) no modulatory effect was observed. OT shifted the ATP concentration-response curve downwards with a decrease of 39.8+/-4.2% in the maximal current response and with no significant change of Kd value. This OT-induced inhibition of I(ATP) showed no voltage dependence, and could be blocked by [d(CH(2))(5),Tyr(Me)(2),Thr(4),Tyr-NH(2)(9)]-OVT (d(CH(2))(5)-OVT) (10(-8) mol/L), a specific OT receptor antagonist. Intracellular application of H-9 (4 x 10(-5) mol/L, an inhibitor of protein kinase A) (n=12), BAPTA (10(-2) mol/L, a chelator of calcium ions) (n=4) could reverse the inhibitory effect of extracellular OT (10(-7) mol), while inclusion of H-7 (2 x 10(-5) mol/L, a protein kinase C inhibitior) (n=8) and KN-93 (10(-5) mol/L, an inhibitor of CaMKII) (n=9) in the recording pipette did not affect this effect. The results suggested that OT inhibition on ATP-activated currents was mediated by OT receptors in the membrane of DRG neurons; and this inhibitory effect involved the transduction of intracellular cAMP-PKA and Ca(2+).
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PMID:Modulation by oxytocin of ATP-activated currents in rat dorsal root ganglion neurons. 1238 76

Oxytocin neurons in the supraoptic nucleus (SON) exhibit marked neuronal plasticity during each reproductive cycle. We have previously shown that this neuronal plasticity includes GABAA receptor subunit switching around the time of parturition. Here we focus on addition plasticity in short-term regulatory mechanisms of postsynaptic receptor function before and after parturition, i.e. alterations in metabotropic and allosteric modulation of GABAA receptor activity. Both short- and long-term regulation of the GABAA receptor function affects the electrical behaviour of the oxytocin neurons (Brussaard and Herbison, 2000); however, their causal linkage until recently remained unclear. Non-genomic gonadal steroid feedback to oxytocin neurons is mediated via the neurosteroid allopregnanolone (3 alpha-OH-DHP) that is an allosteric modulator of postsynaptic GABAA receptors. We recently found evidence to support the idea that (1) neurosteroids not only potentiate GABAA receptor function but also prevent its suppression by PKC (Brussaard et al., 2000), and (2) that neurosteroid sensitivity of GABAA receptor is not regulated by subunit switching, but instead, is dependent on the balance between endogenous phosphatase and PKC activity (Koksma et al., 2002). Thus, before pregnancy, the GABAA receptors are sensitive to 3 alpha-OH-DHP, due to a constitutively high level of phosphatase activity. At parturition, endogenous release of oxytocin within the SON shifts the intracellular balance towards a higher level of phosphorylation, leading to 3 alpha-OH-DHP insensitivity of the GABAA receptors. Here we discuss the putative mechanisms underlying these changes in receptor physiology, their causal relations and the functional significance for the hormonal output.
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PMID:Short-term modulation of GABAA receptor function in the adult female rat. 1243 24

In this study, we investigate how neurosteroid sensitivity of GABA(A) receptors (GABA(A)Rs) is regulated. We examined this issue in neurons of the supraoptic nucleus (SON) of the rat and found that, during parturition, the GABA(A)Rs become insensitive to the neurosteroid allopregnanolone attributable to a shift in the balance between the activities of endogenous Ser/Thr phosphatase and PKC. In particular, a constitutive endogenous tone of oxytocin within the SON after parturition suppressed neurosteroid sensitivity of GABA(A)Rs via activation of PKC. Vice versa before parturition, during late pregnancy, application of exogenous oxytocin brings the GABA(A)Rs from a neurosteroid-sensitive mode toward a condition in which the receptors are not sensitive. This indicates that there may be an inverse causal relationship between the extent to which the GABA(A)R or one of its interacting proteins is phosphorylated and the neurosteroid sensitivity of the GABA(A)R. Neurosteroid sensitivity was not affected by changes in subunit composition of GABA(A)Rs known to occur concurrently in these cells.
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PMID:Oxytocin regulates neurosteroid modulation of GABA(A) receptors in supraoptic nucleus around parturition. 1257 7

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

Adaptive responses mediated by the hypothalamus require sustained activation until homeostasis is achieved. Increases in excitatory drive to the magnocellular neuroendocrine cells that mediate these responses, however, result in the activation of a presynaptic metabotropic glutamate receptor (mGluR) that curtails synaptic excitability. Recent evidence that group III mGluRs can be inhibited by protein kinase C prompted us to test the hypothesis that activation of PKC by noradrenaline (NA) inhibits group III mGluRs and increases excitatory synaptic input to these cells. To examine the effects of NA on miniature EPSCs (mEPSCs), we obtained whole-cell recordings from magnocellular vasopressin and oxytocin neurons in the paraventricular nucleus of the hypothalamus. All of the neurons tested in the current study displayed an alpha1 adrenoceptor-mediated increase in mEPSC frequency in response to NA (1-200 microm). The excitatory effects of NA were mimicked by the phorbol ester PMA and blocked by the PKC inhibitor calphostin C. The activation of PKC inhibits the efficacy of group III mGluRs, resulting in an increase in mEPSC frequency in response to a subsequent exposure to NA. By removing feedback inhibition, this mechanism effectively primes the synapses such that subsequent activation is more efficacious. The novel form of synaptic rescaling afforded by this cross-talk between distinct metabotropic receptors provides a means by which ascending catecholamine inputs can facilitate the control of homeostasis by hypothalamic networks.
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PMID:Priming of excitatory synapses by alpha1 adrenoceptor-mediated inhibition of group III metabotropic glutamate receptors. 1286 6

Nongenomic gonadal steroid feedback to oxytocin containing neurons in the supraoptic nucleus of the hypothalamus is mediated via the neurosteroid allopregnanolone (3alpha-OH-DHP) that acts as an allosteric modulator of the postsynaptic GABA(A) receptors. We found evidence to support the idea that neurosteroids not only potentiate GABA(A) receptor function but also prevent its suppression by PKC. In addition, we found that neurosteroid sensitivity of GABA(A) receptor itself is dependent on the balance between endogenous phosphatase and PKC activity and not, as previously suggested, on subunit composition changes of the GABA(A) receptor. These data imply that native GABA(A) receptors are only sensitive to 3alpha-OH-DHP if there is endogenous phosphatase activity. In contrast, when, due to endogenous release of oxytocin in the hypothalamus, the intracellular balance is shifted from high phosphatase activity toward a higher level of PKC-dependent phosphorylation, this leads to 3alpha-OH-DHP-insensitivity of the GABA(A) receptors. How the regulatory mechanisms of the GABA(A) receptor physiology for the hypothalamus may also account for alterations in GABA transmission observed in other brain areas is discussed.
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PMID:Conditional regulation of neurosteroid sensitivity of GABAA receptors. 1499 37

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

1. Effects of neuropeptides of the vasopressin family on Cl(-) secretion have not yet been reported in lung. Using the 16HBE14o- bronchial epithelial cell line, we investigated their action on Cl(-) secretion. 2. In symmetrical Cl(-) solutions, basolateral application of arginine vasotocin (AVT), oxytocin or isotocin induced a transient I(sc) stimulation (I(peak)), whereas arginine vasopressin (AVP) did not. The effects of different Cl(-) channel blockers and of a protein kinase C (PKC) inhibitor suggest that CFTR is involved in I(peak). The calcium-activated K(+) channel (SK4) and the Cl(-)/HCO(-)(3) exchanger favor the driving force for AVT-mediated Cl(-) secretion. The antagonists of V1a (SR49059)- and V1b (SSR149415)-receptors blocked I(peak), while SR121463B, a V2 receptor antagonist, did not. These results point to the stimulation of a V1-like receptor mediating I(peak) and presenting an efficacy order, AVT>oxytocin>isotocin>>AVP. 3. When a serosal to mucosal Cl(-) gradient was applied, AVT and AVP both stimulated I(sc) according to a biphasic profile, I(peak) being followed by a plateau phase (I(plateau)). The pharmacology of I(plateau) suggests that CFTR channels are involved and that Na(+)/K(+)/2Cl(-) is the only transporter associated with I(plateau). dDAVP, a V2 receptor agonist-induced I(plateau) with the same potency as AVP, suggesting the involvement of V2 receptors in the AVP-induced I(plateau). V2 receptors are present on both opposite membranes, while V1-like receptors are mainly expressed on the basolateral membranes. RT-PCR experiments show the expression of V1a, V1b, V2 and vasopressin-activated calcium-mobilizing (VACM) receptors mRNAs.
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PMID:Vasotocin and vasopressin stimulation of the chloride secretion in the human bronchial epithelial cell line, 16HBE14o-. 1568 10

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