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 stimulates a rapid increase in ovine endometrial prostaglandin (PG) F2alpha synthesis. The overall objective of these experiments was to investigate the cellular mechanisms by which oxytocin induces endometrial PGF2alpha synthesis. The objective of experiment 1 was to determine whether G(i) proteins mediate oxytocin-induced PGF2alpha synthesis. Uteri were collected from four ovary-intact ewes on Day 14 postestrus. Caruncular endometrial explants were dissected and subjected to in vitro incubation. Pertussis toxin, an inhibitor of G(i) proteins, had no effect on the ability of oxytocin to induce PGF2alpha synthesis (P > 0.10). The objective of experiment 2 was to determine whether any of the three mitogen-activated protein kinases (MAPKs), extracellular signal regulated protein kinase (ERK1/2), c-Jun N-terminal/stress-activated protein kinase (JNK/SAPK), or p38 MAPK, mediate oxytocin-induced PGF(2alpha) synthesis. Eleven ovary-intact ewes were given an injection of oxytocin (10 IU; i.v.; n = 5) or physiological saline (i.v.; n = 6) on Day 15 postestrus. Uteri were collected 15 min after injection and caruncular endometrium was dissected. Endometrial homogenates were prepared and subjected to Western blotting. Membranes were probed for both total and phosphorylated forms of all three classes of MAPK. All classes of MAPK were detected in ovine endometrium, but oxytocin treatment had no effect on the expression of these proteins (P > 0.10). ERK1/2 was the only phosphorylated MAPK detected and its concentrations were higher in oxytocin-treated ewes (P < 0.01). The objective of experiment 3 was to further investigate the role of ERK1/2 during oxytocin-induced PGF2alpha synthesis. Uteri were collected from four ovary-intact ewes on Day 14 postestrus. Caruncular endometrial explants were dissected and subjected to in vitro incubation. PD98059, a specific inhibitor of ERK1/2 activity, blocked the ability of oxytocin to stimulate PGF(2alpha synthesis in a dose-dependent manner (P < 0.05). These results indicate that the ovine oxytocin receptor is not coupled to G(i) proteins. These results indicate that oxytocin induces phosphorylation of ERK1/2 and that this MAPK appears to mediate oxytocin-induced PGF2alpha synthesis in ovine endometrium.
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PMID:Cellular mechanisms by which oxytocin mediates ovine endometrial prostaglandin F2alpha synthesis: role of G(i) proteins and mitogen-activated protein kinases. 1156 37

1. We investigated whether catecholamines through activation of alpha(1)-adrenergic receptors (alpha(1)-AR) are involved in mouse uterine contraction at parturition. Myometrial phospholipase C (PLC) activity and uterine contraction were measured in response to noradrenaline (NA), the specific alpha(1)-AR agonist phenylephrine (Phe) and oxytocin (OT). 2. Using the reverse transcription-polymerase chain reaction RT-PCR, we detected the alpha(1a)-AR subtype in late pregnant mouse myometrium. We also detected, by immunoblotting studies, PLCbeta(1), PLCbeta(3) and different alpha-subunits of pertussis toxin-insensitive (Galpha(q/11)) and -sensitive G proteins (Galpha(o/i3), Galpha(i1/2)). 3. Phenylephrine and NA did not alter the myometrial inositol phosphate (InsP) production of late pregnant or parturient mouse. In similar conditions, OT increased InsP production in a dose-dependent manner. Consistent with these results, only OT (10 microM) recruited PLCbeta(1) and PLCbeta(3) to myometrial plasma membranes. The OT-induced InsP response was not altered by pertussis toxin (300 ng ml(-1), 2 h pretreatment), suggesting the involvement of a member of the Galpha(q) family. 4. Noradrenaline and Phe failed to increase uterine contraction at late pregnancy and at parturition. In contrast, OT induced uterine contraction in a dose-dependent manner with maximal increase (400 %) at a concentration of 1 microM. 5. The results indicate that OT receptors (OTR) but not alpha(1)-AR are linked to myometrial PLC activation and uterine contraction in late pregnant and parturient mouse. This discrepancy between mouse and other mammals could be attributed to the alpha(1)-AR subtype expressed in myometrium at this time.
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PMID:Catecholamines are not linked to myometrial phospholipase C and uterine contraction in late pregnant and parturient mouse. 1157 62

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

Oxytocin (OT) receptors are important regulators of myometrial contractility. By using the activity of large conductance Ca2+-activated K+ (BKCa) channels as readout, we analyzed OT signaling in cells from nonpregnant (NPM) and pregnant (PM) rat myometrium in detail. In nystatin-perforated whole-cell patches from NPM cells, which leave the intracellular integrity intact, OT transiently increased BKCa-mediated outward currents (Iout). This OT-evoked Iout was caused by the Ca2+ transients in response to the Gq/11-mediated activation of phospholipase C and was inhibited by activation of protein kinase A (PKA). In an open-access whole-cell patch (OAP), the OT-induced transient rise in Iout was disrupted whereas the regulation of BKCa by the cAMP/PKA cascade remained intact. OT counteracted the isoprenaline, i.e. the beta-adrenoceptor/Gs-mediated effect in NPM cells measured in OAP. In contrast, OT further enhanced the beta-adrenoceptor/Gs-mediated effect on BKCa activity in PM cells. All OT effects in the OAP were mediated by pertussis toxin-sensitive Gi proteins and PKA. By quantitative real-time PCR and overexpression of the recombinant protein, we demonstrate that an up-regulation of the Gbetagamma-stimulated adenylyl cyclase II during pregnancy is most likely responsible for this switch. By studying the OT-evoked Iout in nystatin-perforated whole-cell patches of PM cells, we further detected that the OT receptor/Gibetagamma-mediated coactivation of adenylyl cyclase II enhanced the beta-adrenoceptor/Gs-induced suppression of the OT-evoked Ca2+ transients and thus diminishes and self-limits OT-induced contractility. The differential regulation of the PKA-mediated suppression of OT-evoked Ca2+ transients and BKCa activity likely supports uterine quiescence during pregnancy.
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PMID:Oxytocin receptors differentially signal via Gq and Gi proteins in pregnant and nonpregnant rat uterine myocytes: implications for myometrial contractility. 1717 70

Pulsatile neuropeptide secretion is associated with burst firing patterns; however, intracellular signaling cascades leading to bursts remain unclear. We explored mechanisms underlying burst firing in oxytocin (OT) neurons in the supraoptic nucleus in brain slices from lactating rats. Application of 10 pm OT for 30 min or progressively rising OT concentrations from 1 to 100 pm induced burst firing in OT neurons in patch-clamp recordings. Burst generation was blocked by OT antagonist and ionotropic glutamate receptor blockers or tetanus toxin. Blocking G-protein activation with suramin or intracellular GDP-beta-S, but not intracellularly administered antibody against the OT-receptor (OTR) C terminus, blocked bursts. Moreover, pretreatment of slices with pertussis toxin, an inhibitor of G(i/o)-proteins, did not block OT-evoked bursts, suggesting that G(i)/G(o) activation is unnecessary for burst generation. Thus, we further examined G alpha(q/11)-associated signaling pathways in OT-evoked bursts. Inhibition of phospholipase C or RhoA/Rho kinase did not block bursts. Activation of G betagamma subunits using myristoylated G betagamma-binding peptide (mSIRK) caused bursts, whereas intracellularly loaded antibody against G beta subunit blocked OT-evoked bursts. Blocking Src family kinase, but not phosphatidylinositol 3-kinase, occluded OT-evoked bursts. Similar to the effects of OT on EPSCs, mSIRK inhibited tonic EPSCs and elicited EPSC clustering. Finally, suckling caused dissociation of OTRs and G beta subunits from G alpha(q/11) subunits shown by coimmunoprecipitation and immunocytochemistry, supporting crucial roles for OTRs and G betagamma subunits in the milk-ejection reflex. We conclude that G betagamma subunits play a dominant role in burst firing evoked by applied OT or by suckling.
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PMID:Dominant role of betagamma subunits of G-proteins in oxytocin-evoked burst firing. 1731 86

Nesfatin-1 is a recently identified satiety molecule detectable in neurons of the hypothalamus and nucleus of solitary tract (NTS). Immunohistochemical studies revealed nesfatin-1-immunoreactive (irNEF) cells in the Edinger-Westphal nucleus, dorsal motor nucleus of vagus, and caudal raphe nuclei of the rats, in addition to the hypothalamus and NTS reported in the initial study. Double-labeling immunohistochemistry showed that irNEF cells were vasopressin or oxytocin positive in the paraventricular and supraoptic nucleus; cocaine-amphetamine-regulated transcript or tyrosine hydroxylase positive in arcuate nucleus; cocaine-amphetamine-regulated transcript or melanin concentrating hormone positive in the lateral hypothalamus. In the brainstem, irNEF neurons were choline acetyltransferase positive in the Edinger-Westphal nucleus and dorsal motor nucleus of vagus; tyrosine hydroxylase positive in the NTS; and 5-hydroxytryptamine positive in the caudal raphe nucleus. The biological activity of rat nesfatin-1 (1-82) (100 nm) was assessed by the Ca(2+) microfluorometric method. Nesfatin-1 elevated intracellular Ca(2+) concentrations [Ca(2+)](i) in dissociated and cultured hypothalamic neurons. The response was prevented by pretreating the cells with pertussis toxin (100 nm) or Ca(2+)-free solution and by a combination of the L-type and P/Q-type calcium channel blocker verapamil (1 microm) and omega-conotoxin MVIIC (100 nm). The protein kinase A inhibitor KT 5720 (1 microm) suppressed nesfatin-1-induced rise in [Ca(2+)](i). The result shows that irNEF is distributed to several discrete nuclei in the brainstem, in addition to the hypothalamus and NTS reported earlier, and that the peptide interacts with a G protein-coupled receptor, leading to an increase of [Ca(2+)](i), which is linked to protein kinase A activation in cultured rat hypothalamic neurons.
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PMID:Nesfatin-1: distribution and interaction with a G protein-coupled receptor in the rat brain. 1762 99

Selective serotonin reuptake inhibitors (SSRIs), such as Prozac, are used to treat mood disorders. SSRIs attenuate (i.e. desensitize) serotonin 1A (5-HT(1A)) receptor signaling, as demonstrated in rats through decreased release of oxytocin and adrenocorticotropin hormone (ACTH) following 5-HT(1A) receptor stimulation. Maximal therapeutic effects of SSRIs for treatment of mood disorders, as well as effects on hypothalamic 5-HT(1A) receptor signaling in animals, take 1 to 2 weeks to develop. Estradiol also attenuates 5-HT(1A) receptor signaling, but, in rats, these effects occur within 2 days; thus, estrogens or selective estrogen receptor modulators may serve as useful short-term tools to accelerate desensitization of 5-HT(1A) receptors in response to SSRIs if candidate estrogen receptor targets in the hypothalamus are identified. We found high levels of GPR30, which has been identified recently as a pertussis-toxin (PTX) sensitive G-protein-coupled estrogen receptor, in the hypothalamic paraventricular nucleus (PVN) of rats. Double-label immunohistochemistry revealed that GPR30 co-localizes with 5-HT(1A) receptors, corticotrophin releasing factor (CRF) and oxytocin in neurons in the PVN. Pretreatment with PTX to the PVN before peripheral injections of 17-beta-estradiol 3-benzoate completely prevented the reduction of the oxytocin response to the 5-HT(1A) receptor agonist, (+)-8-hydroxy-2-dipropylaminotetralin (DPAT). Treatment with the selective GRP30 agonist, G-1, attenuated 5-HT(1A) receptor signaling in the PVN as measured by an attenuated oxytocin (by 29%) and ACTH (by 31%) response to DPAT. This study indicates that a putative extra-nuclear estrogen receptor, GPR30, may play a role in estradiol-mediated attenuation of 5-HT(1A) receptor signaling, and potentially in accelerating the effects of SSRIs in treatment of mood disorders.
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PMID:Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus. 1909 43

The actions of the endogenous peptide nociceptin (PNOC; previously abbreviated as N/OFQ) on the myometrium have not been investigated previously. Our aim was to study the presence and functional role of PNOC in the modulation of uterine contractility in pregnant rats at term. The presence of PNOC and its receptors (OPRL1; previously called NOP) in the uterus were detected by radioimmunoassay and radioligand-binding experiments. The PNOC-stimulated G protein activation was assessed by a [(35)S]GTPgammaS-binding technique. The effects of PNOC in uterine rings precontracted with KCl or oxytocin were also tested in vitro. Uterine levels of cAMP were measured by enzyme immunoassay. The K(+) channel blockers tetraethylammonium and paxilline were used to study the role of K(+) channels in mediating the uterine effects of PNOC. Both PNOC and OPRL1 were present in the uterus. PNOC revealed a maximum contraction inhibition of approximately 30%, which was increased to 40% by naloxone. Naloxone and pertussis toxin significantly attenuated the G protein-stimulating effect of PNOC. The uterine cAMP levels were elevated by PNOC and naloxone and after preincubation with pertussis toxin. Tetraethylammonium and paxilline reduced the contraction-inhibiting effect of PNOC and naloxone to approximately 10% and 15%, respectively. We presume that PNOC plays a role in regulating uterine contractility at term. Its effect is mediated partly by stimulatory heterotrimeric G (G(s)) proteins coupled to OPRL1 receptors and elevated cAMP levels, and also by Ca(2+)-dependent K(+) channels. Our results demonstrate a novel action and signaling pathway for PNOC that might be a potential drug target.
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PMID:Nociceptin inhibits uterine contractions in term-pregnant rats by signaling through multiple pathways. 2023 32

Oxytocin receptor is a seven transmembrane receptor widely expressed in the CNS that triggers G(i) or G(q) protein-mediated signaling cascades leading to the regulation of a variety of neuroendocrine and cognitive functions. We decided to investigate whether and how the promiscuous receptor/G protein coupling affects neuronal excitability. As an experimental model, we used the immortalized gonadotropin-releasing hormone-positive GN11 cell line displaying the features of immature, migrating olfactory neurons. Using RT-PCR analysis, we detected the presence of oxytocin receptors whose stimulation by oxytocin led to the accumulation of inositol phosphates and to the inhibition of cell proliferation, and the expression of several inward rectifier (IR) K+ channel subtypes. Moreover, electrophysiological and pharmacological inspections using whole-cell patch-clamp recordings evidenced that in GN11 cells, IR channel subtypes are responsive to oxytocin. In particular, we found that: (i) peptide activation of receptor either inhibited or stimulated IR conductances, and (ii) IR current inhibition was mediated by a pertussis toxin-resistant G protein presumably of the G(q/11) subtype, and by phospholipase C, whereas IR current activation was achieved via receptor coupling to a pertussis toxin-sensitive G(i/o) protein. The findings suggest that neuronal excitability might be tuned by a single peptide receptor that mediates opposing effects on distinct K+ channels through the promiscuous coupling to different G proteins.
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PMID:Dual modulation of inward rectifier potassium currents in olfactory neuronal cells by promiscuous G protein coupling of the oxytocin receptor. 2055 24

Expression of genes that encode oxytocin (OXT) and vasopressin (AVP) and their cognate receptors in normal and diseased prostates are only partially characterized. Reverse transcription and PCR were used to examine the expression of these genes in normal prostate epithelial and stromal cell lines, k-ras-transformed prostate epithelial cell lines, and in four prostate cancer cell lines. Secreted and cell-associated OXT peptide was measured by an enzyme immunoassay. OXT and its receptor (OXTR) were expressed in all eight prostate cell lines. Cell-associated OXT peptide was also found in all prostate epithelial cell lines except in DU145 cells. Neither AVP nor its cognate receptors (V1a receptor and V2 receptor) were expressed in any prostate cell line examined. These data point to the OXTR as the primary target of OXT and AVP, and suggest that OXT might be an autocrine/paracrine regulator in human prostate. We found that OXT induces the migration of PC3 and PC3M, but not DU145 prostate cancer cells. The effect of OXT is distinct from the epidermal growth factor (EGF)-induced migration of prostate cancer cells, in which ERK1/2 and EGF receptor kinase activities were required. When cells were pretreated with pertussis toxin, the effect of OXT, but not EGF, on cell migration was abolished. Pretreatment with the cyclic AMP analogue, 8-Br-cAMP, did not affect OXT-induced cell migration, which eliminated the nonspecific effect of pertussis toxin. We conclude that a Gi-dependent mechanism is involved in OXTR-mediated migration of prostate cancer cells, and indicates a role for OXTR in prostate cancer metastasis.
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PMID:Oxytocin induces the migration of prostate cancer cells: involvement of the Gi-coupled signaling pathway. 2066 60

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