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

In the ruminant ovary, synthesis and secretion of oxytocin begin in the granulosa cells of the preovulatory follicle and are markedly stimulated by the surge of LH and FSH. Luteinization of the granulosa cells results in a further increase in oxytocin gene expression, but translation of mRNA appears to be retarded because the peak concentration of luteal oxytocin occurs later than the maximal accumulation of the message. Several hormones have been shown to stimulate oxytocin secretion from granulosa and luteal cells in vivo or in vitro. However, the role of prostaglandin F2 alpha (PGF2 alpha) in regulating luteal oxytocin secretion has perhaps received more study than other hormones. The mechanism of action of PGF2 alpha has been shown to encompass a phosphoinositide cascade and activation of protein kinase C, events that are associated with luteal secretion of oxytocin. Protein kinase C phosphorylation of the actin-binding protein myristolated alanine-rich C kinase substrate (MARCKS) may be required for exocytosis of oxytocin.
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PMID:Dynamics of molecular mechanisms underlying ovarian oxytocin secretion. 762 28

A physiological role for oxytocin in stimulating uterine contractions during labour is well accepted, but has not yet been well defined. Oxytocin activates phospholipase C to produce inositol 1,4,5-trisphosphate, which releases Ca2+ from intracellular stores. There is considerable evidence that G-proteins are involved in this signalling pathway. The objectives of the present study were to determine the mechanisms of action of oxytocin in human myometrium. We have measured the effect of oxytocin on the formation of inositol phosphates (InsPs) in cultured human myometrial cells labelled with [3H] inositol and on changes in intracellular free Ca2+ concentration ([Ca2+i]) in single cells using a dynamic calcium imaging system. Pertussis toxin was used to obtain information on the G-proteins involved. Oxytocin induced InsPs formation and [Ca2+i] mobilisation in a concentration-dependent manner in human myometrial cells. Our data suggest that two distinct types of G-proteins are involved in the oxytocin response: one most probably a member of the Gq family (pertussis toxin-resistant) and another of the Gi family (pertussis toxin-sensitive). Using Western blotting, we have found that the pertussis toxin-resistant G-proteins alpha(q), alpha(11) and alpha(2), and pertussis toxin-sensitive alpha(i1), alpha(i2), and alpha(i3) are expressed in these cells. We have also detected the phospholipase C isoforms beta(1), beta(2) and beta(3) which are regulated by G-proteins, and phospholipase C isoforms gamma(1) and gamma(2), regulated by receptor tyrosine kinase pathways. However, oxytocin does not stimulate tyrosine phosphorylation in myometrial cells. Extracellular Ca2+ does not play a direct role in the activation of phospholipase C by oxytocin. Protein kinase C causes a strong inhibitory feedback on the oxytocin pathway: protein kinase C activators abolish the response to oxytocin while inhibitors potentiate it. Oxytocin responsiveness is upregulated by incubating the cells in the presence of oestradiol. This effect is reversed by the anti-oestrogen tamoxifen. Oestrogens exert their effects on the oxytocin pathway at a postreceptor level, possibly by affecting the expression of G-proteins and/or phospholipase C isoforms.
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PMID:Oxytocin signalling in human myometrium. 871 98

Oxytocin receptor (OTR) gene transcription has predominantly been thought to be regulated by estrogen. However, the continuous presence of receptors in certain brain regions after gonadectomy suggests the existence of alternate mechanisms of regulation. We have cloned and sequenced 4 kb of 5'-flanking DNA of the rat OTR gene and identified an internal segment which was absent in the initial publication of this promoter sequence. Sequence analysis of this segment, as well as of a novel upstream region, revealed the presence of a CRE as well as several other potential regulatory elements, including AP-1, AP-2, AP-3, AP-4 sites, an ERE, and a half-SRE (SRE/2). The effects of phorbol 12-myristate 13-acetate (PMA), forskolin, and NGF treatment on this promoter were tested in transfection experiments in MCF7 and SK-N-SH cells. Transcription of the full-length OTR promoter was induced by forskolin and by the phorbol ester PMA, and a synergistic (17-fold) effect was observed in MCF7 cells treated with both agents. Receptor binding studies using the OTR antagonist 125I-labeled ornithine vasotocin, and Western blot analyses of OTRs in MCF7 cells, showed that PMA and forskolin also increased the density of endogenous human oxytocin receptors. Mutational analyses of the CRE and half-SRE sites in this promoter indicated that these elements function as enhancers and support forskolin and NGF effects, respectively, on transcription. These studies have identified a novel region of the rat OTR promoter containing elements which impart cAMP and/or phorbol ester inducibility of OTR gene transcription. A potential role of the PKA and/or PKC pathways in OTR gene regulation is suggested.
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PMID:NGF, cyclic AMP, and phorbol esters regulate oxytocin receptor gene transcription in SK-N-SH and MCF7 cells. 947 29

The neuropeptide oxytocin can depolarize parasympathetic preganglionic neurons in the dorsal motor nucleus of the vagus nerve of the rat by generating a sustained inward current, which is sodium-dependent and tetrodotoxin-insensitive. The second messenger activated by oxytocin receptor binding is, however, not yet known. In the present study, we attempted to characterize it by using the whole-cell recording technique and brainstem slices. When loaded with GTP-gamma-S, a non-hydrolysable analogue of GTP, vagal neurons generated a persistent inward current in the absence of agonist and the oxytocin effect was suppressed, suggesting that the peptide-evoked current was mediated by G-protein activation. Loading vagal neurons with the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N',-tetraacetic acid (BAPTA) suppressed a calcium-dependent, slowly decaying potassium aftercurrent but did not affect the oxytocin response, suggesting that the latter was not mediated by an agonist-induced increase in the intracellular calcium concentration. Protein kinase C (PKC) activation was probably not involved, since the peptide-evoked current was not modified by loading neurons with the PKC inhibitor H7. Thus, the oxytocin-evoked current in vagal neurons was probably not mediated by phospholipase C-beta (PLC-beta) activation. Loading neurons with 8-Br-cAMP or with an adenylyl cyclase activator (forskolin) reduced the oxytocin-evoked current by about half. SQ 22536, an adenylyl cyclase inhibitor, reduced this current by a similar amount. However, the peptide-evoked current was unaffected by Rp-cAMPS and Sp-cAMPS, an inhibitor and an activator, respectively, of cAMP-dependent protein kinase (PKA). We suggest that oxytocin activates two distinct signalling pathways in vagal neurons: one which is cAMP-dependent, but PKA-independent, and one, unidentified, which is PLC-beta-and cAMP-independent. Each pathway accounts for about half of the peptide effect and both appear to involve G-protein activation.
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PMID:The oxytocin-induced inward current in vagal neurons of the rat is mediated by G protein activation but not by an increase in the intracellular calcium concentration. 951 66

The stimulatory effect of noradrenaline (NA) as well as oxytocin (OT) on bovine endometrial prostaglandin (PG) F2alpha production, and the intracellular mechanisms of their actions, were investigated in cultured bovine endometrial cells (a mixture of epithelial, stromal, and glandular cells). The cells were cultured in Dulbecco's Modified Eagle's medium and Ham's F-12 medium (1:1 [v:v]) with 10% calf serum. When the cells reached confluence, the culture medium was replaced with fresh medium with 0.1% BSA and various doses of NA (10(-8)-10(-4) M). NA stimulated PGF2alpha production in a dose-dependent manner (p < 0.05). To evaluate the intracellular mechanisms of NA and OT actions, the cells were treated with forskolin (an activator of adenylate cyclase), phorbol 12-myristate 13-acetate (PMA, an activator of protein kinase [PK] C), Rp-cAMP (a competitive cAMP antagonist and an inhibitor of PKA), U-73122 (an inhibitor of phospholipase [PL] C), or anthranilic acid (ACA, an inhibitor of PLA2). Forskolin and PMA stimulated PGF2alpha production in a dose-dependent manner (p < 0.05). Rp-cAMP completely inhibited (p < 0.001) the NA-induced, but not the OT-induced, PGF2alpha production. Although U-73122 inhibited only OT-induced PGF2alpha production (p < 0.001), ACA completely stopped the actions of NA and OT. The overall results indicate that NA as well as OT is involved in the regulation of the endometrial PGF2alpha production in cattle and that the stimulatory effects of NA and OT on PGF2alpha production are mediated via the PKA and PKC pathways, respectively.
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PMID:Noradrenaline stimulates the production of prostaglandin f2alpha in cultured bovine endometrial cells. 991 91

The present study examined how arginine vasopressin (AVP) affects nitric oxide (NO) metabolism in cultured rat glomerular mesangial cells (GMC). GMC were incubated with test agents and nitrite, and intracellular cGMP content, inducible nitric oxide synthase (iNOS) mRNA, and iNOS protein were analyzed by the Griess method, enzyme immunoassay, and Northern and Western blotting, respectively. AVP inhibited lipopolysaccharide (LPS)- and interleukin-1beta (IL-1beta)-induced nitrite production in a dose- and time-dependent manner, with concomitant changes in cGMP content, iNOS mRNA, and iNOS protein. This inhibition by AVP was reversed by V1- but not by oxytocin-receptor antagonist. Inhibition by AVP was also reproduced on LPS and interferon-gamma (IFN-gamma). Protein kinase C (PKC) inhibitors reversed AVP inhibition, whereas PKC activator inhibited nitrite production. Although dexamethasone and pyrrolidinedithiocarbamate (PDTC), inhibitors of nuclear factor-kappaB, inhibited nitrite production, further inhibition by AVP was not observed. AVP did not show further inhibition of nitrite production with actinomycin D, an inhibitor of transcription, or cycloheximide, an inhibitor of protein synthesis. In conclusion, AVP inhibits LPS- and IL-1beta-induced NO production through a V1 receptor. The inhibitory action of AVP involves both the activation of PKC and the transcription of iNOS mRNA in cultured rat GMC.
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PMID:AVP inhibits LPS- and IL-1beta-stimulated NO and cGMP via V1 receptor in cultured rat mesangial cells. 1007 Jan 67

Oxytocin (OT) receptors (OTRs) have been demonstrated in a number of human breast tumors and tumor cells, but it was not clear whether the receptors were functional. We examined the regulation and function of OTR in a tumor cell line, Hs578T, derived from human breast. These cells expressed moderate levels of OTR when cultured in 10% FBS, as demonstrated by RT-PCR and binding analyses. Serum deprivation resulted in the loss of OTRs, with no effect on cell viability. Restoration of serum and addition of 1 microM dexamethasone (DEX) increased OTR levels by about 9-fold. Up-regulation was blocked by the addition of phospholipase C and PKC inhibitors. Serum/DEX treatment also increased steady state OTR messenger RNA levels. OT increased intracellular Ca2+ in a time- and dose-responsive manner, and the effects of OT were lost when OTRs were down-regulated by serum starvation. Serum/DEX up-regulation of OTR restored the responsiveness to OT. OT also stimulated ERK-2 (extracellular signal-regulated protein kinase) phosphorylation and PGE2 synthesis in Hs578T cells. In addition to showing that OTRs in the breast tumor cells are functional, these studies show that Hs578T cells can be used to study molecular regulation of OTR gene expression and intracellular signaling pathways stimulated by OT.
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PMID:Demonstration of functional oxytocin receptors in human breast Hs578T cells and their up-regulation through a protein kinase C-dependent pathway. 1021 79

Objectives were to examine how the conceptus and recombinant bovine interferon-tau (rbIFN-tau) regulate intracellular components of the PGF(2a) synthetic pathway and to determine if arachidonic acid (AA) is limiting in endometrial tissue of pregnant cows. In Experiment 1, uteri were collected from either cyclic or pregnant dairy cows on Day 17 post-estrus. Intercaruncular explants were dissected and incubated for 60 min to quantify PGF(2a) production in response to oxytocin (10(-6) M), A23187 (10(-5) M), melittin (10(-5) M), and phorbol 12, 13 dibutyrate (PDBu, 10(-6) M). Additional explants from the same cows were incubated for 24 h with and without AA. Oxytocin and A23187 did not stimulate PGF(2a) in explants from either cyclic or pregnant cows. Both PDBu, melittin, and A23187 + melittin stimulated PGF(2a) production in explants of cyclic cows, but not in explants of pregnant cows. The addition of AA to explant cultures for 24 hr did not increase PGF(2a) production during a subsequent 60-min incubation. In Experiment 2, explants were collected from cows that received intrauterine infusions of either BSA (1.9 mg/1.2 ml) or rbIFN-tau (0.2 mg rbIFN-tau + 1.7 mg BSA/1.2 ml) twice a day from Days 14 to 17 of the estrous cycle. Treatments of rbIFN-tau attenuated PGF(2a) secretion induced by in vitro PDBu and A23187 treatments. However, rbIFN-tau treatment in vivo had no effect on the in vitro induction of PGF(2a) secretion by melittin. IFN-tau may regulate the PGF(2a) synthetic pathway by reducing activity of PKC or PKC mediated events.
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PMID:Intracellular regulation of endometrial PGF(2a) and PGE(2) production in dairy cows during early pregnancy and following treatment with recombinant interferon-tau. 1076 76

The A1 catecholamine neurons of the caudal ventrolateral medulla transmit hemodynamic information to the vasopressin (VP) neurons in the hypothalamus. These neurons corelease ATP with norepinephrine. Perifused explants of the hypothalamoneurohypophyseal system were used to investigate the role of these substances on VP release. ATP (100 micrometer) increased VP release 1.5-fold (p = 0.027). The response was rapid but unsustained. It was blocked by the P(2) receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). The alpha(1)-adrenergic agonist phenylephrine (PE; 100 micrometer) also increased VP release by 1.5-fold (p = 0.014). Again, the response was rapid and unsustained. However, simultaneous perifusion of explants with ATP (100 micrometer) and PE (100 micrometer) resulted in a threefold to fourfold increase in VP release, which was sustained for as long as 4 hr. There was a similar synergistic effect of ATP and PE on oxytocin release. Interestingly, the synergistic response was delayed approximately 40 min relative to the response to either agent alone. Several experiments were performed to elucidate the cellular mechanisms of this synergism. The effect was blocked by PPADS, a protein kinase C inhibitor (bisindolylmaleimide I HCl), and actinomycin, an inhibitor of gene transcription. These data suggest that P(2X) receptor activation, PKC-mediated phosphorylation, and gene transcription are required for the synergistic response. The marked synergism of these coreleased agents is probably important to achieve sustained increases in plasma VP in response to prolonged hypotension. These observations may also have broad applications to CNS function, because ATP may be coreleased at noradrenergic synapses throughout the CNS.
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PMID:Purinergic and adrenergic agonists synergize in stimulating vasopressin and oxytocin release. 1110 96

Oxytocinase (OTase) degrades several small peptides such as oxytocin (OT), and thus plays important roles in fetal development and maintenance of human homeostasis during pregnancy. The physiological effects of OT are mediated via its receptor (OTR). Although the interactions between OT and OTR have studied extensively, the relationship to OTase remains to be clarified. It is known that human umbilical vascular endothelial cells express OTR messenger RNA; therefore, they were selected for examination of this question in the present study. RT-PCR experiments confirmed the existence of messenger RNA for OTase, and assessment of protein levels and activity clarified that OT increases the activity of OTase at the cell surface via binding to OTR. This stimulation appears to involve translocation of OTase from cytosolic to the cell surface in response to cellular signal transduction pathways linked to the OTR. Protein kinase C stimulation significantly increased the cell surface activity of OTase, whereas its inhibition resulted in reduction. In summary, our findings provide clear evidence that OT triggers directly OTase translocation in human umbilical vascular endothelial cells via a protein kinase C-dependent pathway coupled to OTR.
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PMID:Oxytocin stimulates the translocation of oxytocinase of human vascular endothelial cells via activation of oxytocin receptors. 1110 58


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