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)

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

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

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

Regulated gene expression in single neurons can be linked to biophysical events and behavior in the case of estrogen-regulated gene expression in neurons in the ventrolateral portion of the ventromedial nucleus (VMN) of the hypothalamus. These cells are essential for lordosis behavior. What genes are coexpressed in neurons that have high levels of mRNAs for estrogen receptors (ERs)? We have been able to isolate and measure certain mRNAs from individual VMN neurons collected from rat hypothalamus. Large numbers of neurons express mRNA for ERalpha, but these neurons are not identical with the population of VMN neurons expressing the likely gene duplication product, ERbeta. An extremely high proportion of neurons expressing either ER also coexpress mRNA for the oxytocin receptor (OTR). This fact matches the known participation of oxytocin binding and signaling in sexual and affiliative behaviors. In view of data that ER and OTR can signal through PKCs, we looked at coexpression of selected PKCs in the same individual neurons. The most discriminating analysis was for triple coexpression of ERs, OTR, and each selected PKC isoform. These patterns of triple coexpression were significantly different for male vs. female VMN neurons. Further, individual neurons expressing ERalpha could distribute their signaling across the various PKC isoforms differently in different cells, whereas the reverse was not true. These findings and this methodology establish the basis for systematic linkage of the brain's hormone-sensitive signaling pathways to biophysical and behavioral mechanisms in a well studied mammalian system.
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PMID:Sex and estrogenic effects on coexpression of mRNAs in single ventromedial hypothalamic neurons. 1618 84

Oxytocin (OT) is a potent uterine agonist. Its receptor (OTR) is a G protein-coupled receptor that is downregulated by prolonged exposure to OT. We hypothesized that activation of PKC mediated this OT-induced decrease in OTR expression. Diminished PKC activity in late pregnancy could underlie the increased expression of uterine OTR preceding labor onset. Using cell cultures of transformed human uterine myocytes, we determined the effects of PKC agonists and antagonists on the expression of OTR. We also explored the effects of overexpression of activator protein-1 (AP-1, a mediator of many PKC- and phorbol ester-induced effects) using adenoviral expression vectors for the AP-1 subunits c-Jun and c-Fos. Stimulation of PKC using the phorbol ester 12-O-tetradecanoylphorbol 13-acetate caused a rapid, significant (P < or = 0.05) increase in c-Jun and c-Fos concentrations but a significant decrease in mRNA for OTR within 6 h followed by a significant decrease in OT binding by 24 h. Adenoviral infection of the cells with expression vectors for c-Jun and c-Fos increased the AP-1 subunits but had no effect on OTR expression. Furthermore, there were no changes in c-Fos or c-Jun levels in human intrauterine tissues around the time of labor onset, as measured by Western analyses. We conclude that phorbol ester treatment decreases OTR expression, likely through a mechanism that does not involve AP-1.
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PMID:Phorbol ester treatment of human myometrial cells suppresses expression of oxytocin receptor through a mechanism that does not involve activator protein-1. 1675 45

Experiments were conducted to characterize the effects of oxytocin (OT) and vasopressin (VP) on epithelial cells isolated from human (1 degree HVD) and porcine (1 degree PVD) vas deferens and an immortalized epithelial cell line derived from porcine vas deferens (PVD9902 cells). Cultured monolayers were assessed in modified Ussing flux chambers and the OT- or VP-induced change in short circuit current (I(SC)) was recorded. All cell types responded to basolateral OT or VP with a transient increase in I(SC) that reached a peak of 3-5 microA cm(-2). Concentration-response curves constructed with 1 degree PVD and PVD9902 cells revealed that the apparent K(D) (k(app)) for OT was approximately 100-fold less than the k(app) for VP. Amplicons for the OT receptor (OXTR) and vasopressin type 2 and type 1a receptors (AVPR2 and AVPR1A) were generated with RT-PCR and the identification of each amplicon confirmed by sequence analysis. A selective antagonist for OXTR and AVPR1A fully blocked the effects of OT and partially blocked the effects of VP when assessed in both 1 degree PVD and PVD9902 monolayers. APVR2 antagonists blocked the effects of low (< or =30 nM) but not high concentrations of VP, indicating that VP was affecting both AVPR2 and a second receptor subtype, likely OXTR or AVPR1A. Experiments employing chelerythrine demonstrated that OT stimulation of vas deferens monolayers requires PKC activity. Alternatively, VP (but not OT) increased the accumulation of cytosolic cAMP in vas deferens epithelial cells. Results from this study demonstrate that OT and VP can modulate ion transport across vas deferens epithelia by independent mechanisms. OT and VP have the potential to acutely change the environment to which sperm are exposed and thus, have the potential to affect male fertility.
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PMID:Oxytocin and vasopressin stimulate anion secretion by human and porcine vas deferens epithelia. 1744 54

Experiments were conducted to further our understanding of the cellular and molecular mechanisms that regulate luteal function in ewes. Inhibition of protein kinase A (PKA) reduced (P < 0.05) secretion of progesterone from both small and large steroidogenic luteal cells. In addition, the relative phosphorylation state of steriodogenic acute regulatory protein (StAR) was more than twice as high (P < 0.05) in large vs small luteal cells. Large steroidogenic luteal cells appear to contain constitutively active PKA and increased concentrations of phosphorylated StAR which play a role in the increased basal rate of secretion of progesterone. To determine if intraluteal secretion of prostaglandin (PG) F2alpha was required for luteolysis, ewes on day 10 of the estrous cycle received intraluteal implants of a biodegradable polymer containing 0, 1 or 10 mg of indomethacin, to prevent intraluteal synthesis of PGF2alpha. On day 18, luteal weights in ewes receiving 1 mg of indomethacin were greater (P < 0.05) than controls and those receiving 10 mg were greater (P < 0.05) than either of the other two groups. Concentrations of progesterone in serum were also increased (P < 0.05) from days 13 to 16 of the estrous cycle in ewes receiving 10 mg of indomethacin. Although not required for decreased production of progesterone at the end of the cycle, intraluteal secretion of PGF2alpha appears to be required for normal luteolysis. To ascertain if oxytocin mediates the indirect effects of PGF2alpha on small luteal cells, the effects of 0, 0.1, 1 or 10 mM oxytocin on intracellular concentrations of calcium were quantified. There was a dose-dependent increase (P < 0.05) in the number of small luteal cells responding to oxytocin. Thus, oxytocin induces increased calcium levels and perhaps apoptotic cell death in small luteal cells. Concentrations of progesterone, similar to those present in corpora lutea (approximately 30 microg/g), prevented the increased intracellular concentrations of calcium (P < 0.05) stimulated by oxytocin in small cells. In large luteal cells the response to progesterone was variable. There was no consistent effect of high quantities of estradiol, testosterone or cortisol in either cell type. It was concluded that normal luteal concentrations of progesterone prevent the oxytocin and perhaps the PGF2alpha-induced increase in the number of small and large luteal cells which respond to these hormones with increased intracellular concentrations of calcium. In summary, large ovine luteal cells produce high basal levels of progesterone, at least in part, due to a constituitively active form of PKA and an enhanced phosphorylation state of StAR. During luteolysis PGF2alpha of uterine origin reduces the secretion of progesterone from the corpus luteum, but intraluteal production of PGF2alpha is required for normal luteolysis. Binding of PGF2alpha to receptors on large luteal cells stimulates the secretion of oxytocin which appears to activate PKC and may also inhibit steroidogenesis in small luteal cells. PGF2alpha also activates COX-2 in large luteal cells which leads to secretion of PGF2alpha. Once intraluteal concentrations of progesterone have decreased, oxytocin binding to its receptors on small luteal cells also results in increased levels of intracellular calcium and presumably apoptosis. Increased secretion of PGF2alpha from large luteal cells activates calcium channels which likely results in apoptotic death of this cell type.
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PMID:Judge, jury and executioner: the auto-regulation of luteal function. 1749 Nov 48

The work deals with the study of molecular and membrane mechanisms of uterotonic peptide hormone oxytocin action on Ca ions homeostasis in the uterus myocites and activity of passive and active transport systems of this cation, localized in the myometrium subcellular structures. Biochemical mechanisms of additional Ca2+ influx into the myometrium cells from extracellular environment activated by oxytocin and thapsigargin were determined. Such Ca2+ influx has got the name of capacitative cation entry (CCE), or which is activated by intracellular store depletion (store-operated calcium entry). It was shown that cells from the nonpregnant human myometrium and PHM1-41 cells (immortalized pregnant human myometrial cells) expressed endogenous hTrpC1, 3, 4, 6 and 7 mRNA. The membrane-permeable derivative of diacylglycerol (OAG) stimulated an increase in oscillations of intracellular free Ca2+ concentration in PHM1-41 and myometrium cells. OAG-induced Ca2+ -oscillations were not affected by inhibition of PKC. It was proved that hTrpC channels take part in the regulation of free Ca ions concentration in the myometrium cells. On the basis of results of experiments, conducted on myometrium plasma membrane fraction, the conclusion was made that oxytocin does not influence the passive Ca2+ efflux. It was shown that peptyde hormone partially inhibited Ca2+ accumulation in plasma membrane fraction. Oxytocin also partially inhibited endoplasmic reticulum calcium pump activity of the myometrium cells. The conceptual pattern of myometrial Ca2+ exchange regulation by oxytocin is offered.
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PMID:[Oxytocin and its role in the control of intracellular level of calcium ions in the myometrium]. 2068 39

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