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) induces PG synthesis by both uterine endometrial and amnion cells. We showed previously that CHO cells stably transfected with the rat oxytocin receptor (CHO-OTR cells) also synthesize PGE2 in response to OT. In the present work we have demonstrated that OTRs are coupled to both Gi and Gq/11, using immunoprecipitation of solubilized OTR complexes and ADP ribosylation. OT treatment caused the rapid phosphorylation of extracellular signal-regulated protein kinase 2 (ERK2 or p42MAPK), which was partially inhibited by pertussis toxin (PTX), consistent with OTR-Gi coupling. The PTX-insensitive portion of ERK2 phosphorylation was linked to Gq, as inhibitors of both phospholipase C (U-73122) and protein kinase C (GF-109203X) blocked OT-induced ERK2 phosphorylation. OT-stimulated c-fos expression was also mediated by ERK2 phosphorylation. The ERK-c-fos pathway has been shown to be associated with cell proliferation, but OT had no effect on [3H]thymidine uptake by CHO-OTR cells. However, inhibition of OT-induced ERK2 phosphorylation with an ERK kinase inhibitor (PD-98059) markedly reduced OT-stimulated PGE2 synthesis, pointing to the importance of ERK2 activation in OT action.
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PMID:ERK2 mediates oxytocin-stimulated PGE2 synthesis. 957 24

To determine whether chronic oxytocin pretreatment inhibits adenylyl cyclase, we compared adenylyl cyclase activity in membranes prepared from cultured, immortalized rat myometrial cells that were untreated or pretreated for 24 h with oxytocin. Chronic oxytocin pretreatment (1 x 10(-5) M for 24 h) attenuated basal, guanosine triphosphate (1 x 10(-5) M)-, isoproterenol (1 x 10(-4) M)-, forskolin (1 x 10(-5) M)-, MnCl2 (20 mM)- or NaF (1 x 10(-2) M)-stimulated adenylyl cyclase activity by 27 +/- 5% to 39 +/- 11% (n = 6, p < 0.05). Oxytocin pretreatment for 2 h (n = 5) did not produce a significant effect. To understand the mechanism by which oxytocin pretreatment decreased activity of the adenylyl cyclase pathway, we compared effects of pretreatment with either oxytocin or phenylephrine on adenylyl cyclase activity and determined the effects of Gi inhibition and protein kinase C (PKC) depletion. Chronic (24 h) phenylephrine pretreatment (1 x 10(-4) M) had effects similar to those of oxytocin pretreatment (1 x 10(-5) M). PKC depletion with phorbol 12-myristate 13-acetate (1 x 10(-6) M, 41 h) prevented attenuation of adenylyl cyclase activity by oxytocin pretreatment (1 x 10(-5) M for 24 h). Inhibition of Gi by pertussis toxin pretreatment (1.25 microg/ml, 41 h) had no significant effect. These findings suggest that chronic oxytocin pretreatment desensitizes the adenylyl cyclase pathway by a cross-regulatory mechanism that involves activation of Gq and PKC.
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PMID:Chronic oxytocin pretreatment inhibits adenylyl cyclase activity in cultured rat myometrial cells. 978 Mar 16

The role of placental CRH in human pregnancy is currently unknown. The myometrium expresses CRH receptors that during pregnancy become coupled to adenylate cyclase. Oxytocin (OT) is one of the main regulators of uterine activity, acting via activation of the inositol triphosphate pathway. In view of the possible cross-talk between the CRH and OT signal transduction pathways we have sought to examine in more detail the second messenger mechanisms involved. CRH receptor binding affinity for CRH and activation of adenylate cyclase were reduced in the presence of OT in pregnant (at term, but not preterm) human myometrium. OT action was mediated via pertussis toxin-sensitive G proteins, which directly inhibit adenylate cyclase and, via activation of protein kinase C, phosphorylate the CRH receptor, leading to desensitization. Activation of protein kinase C by OT could be partially inhibited in human pregnant myometrial cells by OT antagonists (F327 and CAP476; 1 microM) or phospholipase C inhibitors (U73122; 10 microM). These results suggest that in term myometrium, CRH receptor function is modulated by OT, leading to reduced biological activity, lower cAMP levels, and a subsequent shift in favor of contractility rather than relaxation.
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PMID:Activation of protein kinase C by oxytocin inhibits the biological activity of the human myometrial corticotropin-releasing hormone receptor at term. 992 81

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

The aim of the present study was to clarify the cellular mechanisms underlying the alpha(2)-adrenoceptor-mediated contraction of porcine myometrium (nonvascular smooth muscle). Acetylcholine (3 nM-1 microM), clonidine (1 nM-10 microM) and 5-bromo-N-[2-imidazolin-2-yl]-6-quinoxalinamine (UK14304) (1 nM-10 microM) in Krebs solution caused a concentration-dependent contraction in the longitudinal muscles of the porcine uterus with similar EC(50) values and maximum responses. A lowered external Ca(2+) concentration and verapamil (10 nM-10 microM) decreased the contractile response to clonidine and UK14304 more markedly than the response to acetylcholine. However, in Kumagai solution, neither clonidine nor UK14304 caused contractile responses, but acetylcholine remained effective. The effects of alpha(2)-adrenoceptor agonists on intracellular Ca(2+) concentration ([Ca(2+)](i)) and smooth muscle force were measured simultaneously using fura-PE3-loaded muscle preparations. Clonidine and UK14304 caused increases in [Ca(2+)](i) and force of the longitudinal muscle. The increases in [Ca(2+)](i) and muscle force were markedly inhibited by verapamil and in Ca(2+)-free solution (EGTA, 1 mM). In the absence of external Ca(2+), clonidine caused only a small increase in [Ca(2+)](i) in Ca(2+)-loaded preparations compared with those increases caused by carbachol, histamine, and oxytocin. Ca(2+) (2.5 mM) caused increases in [Ca(2+)](i) and force of the longitudinal muscles in a Ca(2+)-free high K(+) solution. Clonidine concentration dependently potentiated the Ca(2+)-induced contraction without significantly changing the increase in [Ca(2+)](i), and this potentiation was inhibited by yohimbine. These results suggested that clonidine increases the Ca(2+) sensitivity of the contractile elements through activation of alpha(2)-adrenoceptors. During the development of the contractile response to clonidine (1 microM, 0-5 min), tissue cyclic AMP levels did not change significantly. In vitro treatment with pertussis toxin (1 microg/ml for 2 h) significantly decreased the contraction induced by clonidine without affecting the responses to carbachol and high K(+). The present results indicate that in porcine myometrium, alpha(2)-adrenoceptor stimulation caused contraction of the longitudinal muscles by mechanisms largely dependent on the influx of extracellular Ca(2+), probably through voltage-dependent Ca(2+) channels (VDCCs), and that the potentiation of the Ca(2+) sensitivity of the contractile elements is another mechanism of the contractile responses. These actions involve a pertussis-toxin-sensitive G protein (probably G(i) type) in the signal transduction pathway.
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PMID:The mechanisms of alpha(2)-adrenoceptor agonist-induced contraction in longitudinal muscle of the porcine uterus. 1070 23

Using in situ hybridization and immunoblot analysis, the present studies identified G(z) mRNA and G(z)-protein in the hypothalamic paraventricular nucleus. The role of G(z)-proteins in hypothalamic 5-HT(1A) receptor signaling was examined in vivo. Activation of 5-HT(1A) receptors increases the secretion of oxytocin and ACTH, but not prolactin. Intracerebroventricular infusion (3-4 d) of G(z) antisense oligodeoxynucleotides, with different sequences and different phosphorothioate modification patterns, reduced the levels of G(z)-protein in the hypothalamic paraventricular nucleus, whereas missense oligodeoxynucleotides had no effect. Neither antisense nor missense oligodeoxynucleotide treatment altered basal plasma levels of ACTH, oxytocin, or prolactin, when compared with untreated controls. An antisense-induced decrease in hypothalamic G(z)-protein levels was paralleled by a significant decrease in the oxytocin and ACTH responses to the 5-HT(1A) agonist 8-hydroxy-dipropylamino-tetralin (8-OH-DPAT). In contrast, the prolactin response to 8-OH-DPAT (which cannot be blocked by 5-HT(1A) antagonists) was not inhibited by G(z) antisense oligodeoxynucleotides. G(z)-proteins are the only members of the G(i)/G(o)-protein family that are not inactivated by pertussis toxin. In a control experiment, pertussis toxin treatment (1 microgram/5 microliter, i.c.v.; 48 hr before the 8-OH-DPAT challenge) did not inhibit the ACTH response, potentiated the oxytocin response, and eliminated the prolactin response to 8-OH-DPAT. Thus, pertussis toxin-sensitive G(i)/G(o)-proteins do not mediate the 5-HT(1A) receptor-mediated increase in ACTH and oxytocin secretion. Combined, these studies provide the first in vivo evidence for a key role of G(z)-proteins in coupling hypothalamic 5-HT(1A) receptors to effector mechanisms.
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PMID:Evidence that G(z)-proteins couple to hypothalamic 5-HT(1A) receptors in vivo. 1077 73

Morphine inhibits oxytocin neurones via G(i/o)-protein-linked mu-opioid receptors. Following chronic morphine administration oxytocin cells develop dependence, shown by withdrawal excitation after administration of the opioid antagonist, naloxone. Here, inactivation of G(i/o)-proteins by pre-treatment of morphine-dependent rats with pertussis toxin injected into the left supraoptic nucleus reduced withdrawal-induced Fos protein expression within the injected nucleus by 41+/-10% compared to the contralateral nucleus, indicating that functional G(i/o)-proteins are essential for the development and/or expression of morphine dependence by oxytocin cells in the supraoptic nucleus. In another group of rats, pertussis toxin did not alter the responses to either systemic cholecystokinin administration or systemic hypertonic saline administration, indicating that pertussis toxin does not prevent oxytocin cells from responding to stimuli that are not mediated by G(i/o)-proteins. Finally, pertussis toxin reduced acute morphine inhibition of systemic hypertonic saline-induced Fos protein expression in the supraoptic nucleus, confirming that pertussis toxin effectively inactivates G(i/o)-proteins in the supraoptic nucleus. Thus, the expression of morphine withdrawal excitation by supraoptic nucleus oxytocin cells requires the functional integrity of G(i/o)-proteins within the nucleus.
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PMID:Local injection of pertussis toxin attenuates morphine withdrawal excitation of rat supraoptic nucleus neurones. 1080 81

Histaminergic neurons of the tuberomammillary nucleus (TM) project monosynaptically to the supraoptic nucleus (SON). This projection remains intact in our hypothalamic slices and permits investigation of both brief synaptic responses and the effects of repetitively activating this pathway. SON oxytocin (OX) neurons respond to single TM stimuli with fast IPSPs, whose kinetics resemble those of GABA(A) or glycine receptors. IPSPs were blocked by the Cl(-) channel blocker picrotoxin, but not by bicuculline or strychnine, and by histamine H(2), but not by H(1) or H(3) receptor antagonists, suggesting the presence of an ionotropic histamine receptor and the possible nonspecificity of currently used H(2) antagonists. G-protein mediation of the IPSPs was ruled out using guanosine 5'-O-(2-thiodiphosphate) (GDP-betaS), pertussis toxin, and Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPs), none of which blocked evoked IPSPs. We also investigated the effects of synaptically released histamine on dye coupling and neuronal excitability. One hundred seventy-three OX neurons were Lucifer yellow-injected in horizontal slices. Repetitive TM stimulation (10 Hz, 5-10 min) reduced coupling, an effect blocked by H(2), but not by H(1) or H(3), receptor antagonists. Because H(2) receptors are linked to activation of adenylyl cyclase, TM-stimulated reduction in coupling was blocked by GDP-betaS, pertussis toxin, and Rp-cAMPs and was mimicked by 8-bromo-cAMP, 3-isobutyl-1-methylxanthine, and Sp-cAMP. Membrane potentials of OX and vasopressin neurons were hyperpolarized, accompanied by decreased conductances, in response to bath application of 8-bromo-cAMP but not the membrane-impermeable cAMP. These results suggest that synaptically released histamine, in addition to evoking fast IPSPs in OX cells, mediates a prolonged decrease in excitability and uncoupling of the neurons.
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PMID:Ionotropic histamine receptors and H2 receptors modulate supraoptic oxytocin neuronal excitability and dye coupling. 1131 81

An increase in intracellular Ca2+ ([Ca2+]i) is essential for mammary myoepithelial cells to contract, leading to milk ejection during lactation. In this study, the intracellular signaling leading to the increase in [Ca2+]i in cultured myoepithelial cells from mouse lactating mammary glands was investigated using fura-2 fluorescence ratiometry. [Ca2+]i increased in cultured myoepithelial cells in response to either oxytocin (1 nM) or ATP (10 microM), and the cells then contracted. These [Ca2+]i responses were diminished by treatment with an inhibitor of phospholipase C (> or = 1 microM U73122). Intracellular application of inositol 1,4,5-trisphosphate (IP3: 10 or 100 microM) increased [Ca2+]i. Pretreatment with pertussis toxin (PTX: 0.1 or 1 microgram/ml) inhibited the [Ca2+]i response to ATP, but had less of an effect on the response to oxytocin. These results indicate that oxytocin and purinergic receptors are coupled to PTX-insensitive and PTX-sensitive G proteins, respectively, and that their activation leads to the increase in [Ca2+]i through the release of Ca2+ from IP3-sensitive intracellular stores via the inositol-phospholipid signaling pathway. Furthermore, we found that the [Ca2+]i responses to oxytocin at physiological doses (0.01-0.1 nM) were augmented in the presence of a sub-responsive dose of ATP (1 microM). The activation of purinergic receptors may facilitate myoepithelial cell contraction in milk-ejection responses.
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PMID:Synergistic effects of ATP on oxytocin-induced intracellular Ca2+ response in mouse mammary myoepithelial cells. 1137 69

The actin cytoskeleton is important for stress fiber formation and contributes to the initiation and maintenance of smooth muscle contraction. To determine if oxytocin and lysophosphatidic acid (LPA) induce stress fiber formation, cultured human myometrial cells were exposed to oxytocin (10(-5) M) or LPA (10(-6) M), and filamentous (F) and globular (G) actin pools were stained with fluorescein isothiocyanate-phalloidin and Texas red DNase I, respectively. The F- to G-actin fluorescent-staining ratio was measured by fluorescence microscopy. Oxytocin and LPA increased stress fiber formation, as indicated by an increase in the F- to G-actin fluorescent-staining ratio. The Rho-kinase inhibitor Y-27632 markedly attenuated this increase. Oxytocin-induced stress fiber formation was completely inhibited in the presence of the oxytocin antagonist compound VI. Tyrosine kinase inhibition with tyrphostin A23 partially blocked the increase induced by oxytocin but had no effect on LPA-induced stress fiber formation. Stress fiber formation was not blocked by pertussis toxin, mitogen-activated protein kinase, or protein kinase C inhibitors. Our results show that human myometrial cells respond to oxytocin and LPA with the formation of stress fibers that may be involved in the maintenance of uterine contractions. Rho-kinase appears to be a key signaling factor in this pathway.
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PMID:Oxytocin and lysophosphatidic acid induce stress fiber formation in human myometrial cells via a pathway involving Rho-kinase. 1146 6

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