Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01178 (oxytocin)
 15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The modulation of oxytocin (OT) receptors (OTRs) by estrogen was investigated in the ventromedial hypothalamus by in vitro receptor autoradiography. Treatment of ovariectomized and adrenalectomized rats with various doses of estradiol benzoate (EB) increased OTR binding not only in the ventromedial nuclei of the hypothalamus (VMN), but also in the area lateral to the nuclei (IVMN). After a single injection of EB, OTRs first were induced within the ventrolateral parts of the VMN, and only hours later they appeared in the IVMN. This is consistent with the interpretation that OTRs are first induced within the estrogen-sensitive neurons of the ventrolateral VMN and then are transported laterally out of the nuclei. Two additional experiments confirmed this interpretation. First, local infusion of a low dose (10 micrograms) of the neuronal transport inhibitor vinblastine blocked the appearance of OTRs in the IVMN but did not prevent the induction of OTRs by EB within the nuclei. Second, a knife cut placed lateral to the VMN prevented the spread of OTRs out of the nuclei. However, even after treatment with a high dose of EB (2 x 10 micrograms), progesterone (P) was required for a maximal extension of the area covered by OTRs. Thus, the OTR is an estrogen-induced neurotransmitter receptor that is transported to its site of action, the lateral ventromedial hypothalamus, where it is modulated by P and where estrogen-induced OT immunoreactivity is found.
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PMID:Transport of estrogen-induced oxytocin receptors in the ventromedial hypothalamus. 165 49

The human oxytocin (OT) receptor was stably expressed in 293 embryonic kidney cells (293/OTR), characterized pharmacologically and compared to human uterine myometrial receptors. The cloned receptor is expressed at a reasonably high density (0.82 fmole/microgram protein) and exhibits high affinity for [3H]OT (Kd = 0.32nM), similar to the value found in human myometrial tissue. The rank-order of potency for various antagonist and agonist ligands from several structural classes is also similar between the cloned and native receptor, as seen in a comparison of their inhibitory constants for [3H]OT binding. Agonist affinity at the cloned OT receptor is decreased by guanine nucleotide analogs, demonstrating functional G-protein-coupling. The OT receptor in 293 cells, like in human myometrium, is also coupled to the inositol phosphate pathway. In 293/OTR cells, OT stimulates inositol phosphate accumulation with an EC50 = 4.1 nM, an effect blocked by a potent and selective OT antagonist, L-366,948. Additionally, the cloned receptor in 293 cells desensitizes to high concentrations of OT, similar to the desensitization in myometrial tissue and also described for several other G-protein-coupled receptors. These results illustrate the utility of the 293 cell line for expressing human OT receptors in an environment quite comparable to the native myometrial tissue.
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PMID:Characterization of the human oxytocin receptor stably expressed in 293 human embryonic kidney cells. 747 79

It is considered that steroid hormones, the concentrations of which vary during pregnancy, play an important role in the initiation of delivery. In the present study, we measured intracellular Ca2+ ([Ca2+]i) change following oxytocin stimulation in cultured human myometrial cells with fura-2, a fluorescent Ca2+ indicator. We also studied the effect of the steroid hormones on changes in [Ca2+]i due to oxytocin stimulation. When the [Ca2+]i change due to 10(-6) M oxytocin reached 100%, the addition of 10(-6) M DHAS (dehydroepiandrosterone sulfate) just before the stimulation raised the [Ca2+]i level to 207%, whereas that of 10(-6) M progesterone dropped to 64%. Moreover DHAS accelerated the speed of increase until the maximum response of [Ca2+]i, while progesterone decelerated it. In another study, human myometrial plasma membrane was solubilized in 7.5mM CHAPSO solution and applied to a binding study. Oxytocin receptors of two different molecular weights, namely 350kD(OTR-1) and 39kD(OTR-2), were extracted from solubilized plasma membrane by employing a gel filtration column. Binding assays were performed for OTR-1 and OTR-2 in the presence of DHAS and progesterone (10(-5) M). The results showed that DHAS enhanced the binding affinity of the receptors, whereas progesterone reduced the maximum binding capacity. It is therefore considered that the steroid hormones added just before oxytocin stimulation might act on receptor levels and modify intracellular Ca2+ response over short periods.
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PMID:[Effects of steroid hormones on change in [Ca2+]i following oxytocin stimulation in cultured human myometrial cells, and on myometrial oxytocin receptor]. 839 68

Oxytocin (OT) receptors (OTR) in rabbit amnion increase more than 200-fold at the end of gestation. In the present report, we studied the basis of this up-regulation. Incubation of amnion cells with cortisol (20 nM) for 24 h increased the amount of 125I-labeled OT antagonist bound by 16- to 18-fold. The effects of cortisol were dose and steroid dependent. Administration of glucocorticoid to pregnant does also increased the concentration of OTRs in amnion. The effects of cortisol in vitro were potentiated by the addition of forskolin (50 microM), so that OTR number increased by as much as 182 times. The effects of cortisol and forskolin, either separately or in combination, were inhibited by activation of protein kinase-C or coincubation with transforming growth factor-alpha (10 nM). Cyclosporin-A (5 microM) selectively inhibited cortisol-induced rises in the OTR concentration. The addition of cortisol to amnion cells increased OT-stimulated prostaglandin E2 (PGE2) release almost 100-fold; the combination of forskolin and cortisol increased the PGE2 response to OT about 5600 times. Judging from the greater effects on PGE2 release, these results suggest that forskolin and cortisol up-regulate the signal response mechanism to OT as well as the OTR concentration. The findings show that changes occurring in the amnion in vivo can be mimicked in vitro, and they elucidate the mechanism of up-regulation of OTR concentrations.
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PMID:Up-regulation of oxytocin receptors in rabbit amnion by glucocorticoids: potentiation by cyclic adenosine 3',5'-monophosphate. 840 89

The expression of the oxytocin (OT) receptor (OTR) in breast cancer was studied using newly established anti-OTR monoclonal antibodies. Immunoblotting indicated that the antibody 2F8 recognized a 70K OTR in the pregnant myometrium and breast cancer tissue. Among 57 breast cancer patients, we detected OTR immunoreactivity in 52 (91.2%) by immunohistochemistry using 2F8. Using another monoclonal antibody for different receptor domains, 1-2, the staining profile was identical in all positive samples. Of 52 OTR-positive samples, 28 were diffusely positive (> 80% of cancer cells were stained), and 24 were partially positive (< 80% cells were stained). The ratio of estrogen receptor-positive samples was slightly higher among those that were diffusely positive, but there was no apparent relationship between OTR expression and other clinical parameters. We also confirmed the expression of the OTR in positively stained samples by means of Northern blotting and RT-PCR at the transcription level. The OTR messenger RNA and RT-PCR product were the same size as those in the pregnant myometrium. We also determined the expression of the OTR using flow cytometry in four breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-361, and MDA-MB-468). However, OT had no significant effect on their growth during a short period (7 days) of culture. These findings indicated that the OTR is expressed in breast cancer derived not from the myoepithelium but from the glandular or ductal epithelium; however, the biological function of OT in breast cancer remains to be determined.
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PMID:Investigation of the oxytocin receptor expression in human breast cancer tissue using newly established monoclonal antibodies. 859 29

Oxytocin (OT) receptor (OTR) concentrations were determined in the cervix of nonpregnant cows on cycle Days 0, 3, 7-8, 17, and 19 (n = 3-4 cows each day); [3H]OT was used as the labeled ligand. Mucosal and muscle layers of the cervix were also analyzed separately for both ligand binding and expression of the OTR gene using a newly developed RNase protection assay (RAP). Cellular localization of OTR protein was determined by immunohistochemistry. All regions of cervix from cows at estrus had high concentrations of OTR; in the luteal phase, all were sharply down-regulated. At estrus the mucosal layer had about 30-fold higher concentrations than the muscle layer. OTR mRNA was readily detected by RAP in the mucosa from estrous cows, while much weaker signals were found in the muscle. On Days 7-17, the OTR mRNA signals in both mucosa and muscle were very faint or nondetectable. Thus, there was a good correlation between ligand binding and mRNA expression, which suggests that OTR concentrations are mainly regulated at the transcriptional level. The epithelial cells at the luminal surface of the mucosa were the principal site of immunoreactive OTR; muscle cells showed significantly weaker signals. Previously, OT was found to stimulate prostaglandin (PG) E2 output in vitro in bovine cervical tissues. Since PGE2 is capable of softening the cervix, our findings suggest that OT may have a novel physiological function to cause softening of the bovine cervix mediated by the release of PGE2.
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PMID:Oxytocin receptors in bovine cervix: distribution and gene expression during the estrous cycle. 883 94

The effects of recombinant ovine interferon-tau (IFN-tau) and progesterone on oestrogen-stimulated expression of endometrial receptors for oestrogen (ER), progesterone (PR) and oxytocin (OTR) were determined in ovariectomized ewes. Cyclic ewes (n = 16) were ovariectomized and fitted with uterine catheters on Day 4 of the oestrous cycle (Day O, oestrous) and assigned randomly in 2 x 2-factorial arrangement to receive daily intrauterine injections of either recombinant ovine IFN-tau (roIFN-tau; 2 x 10(7) anti-viral units) or control proteins from Day 11 to Day 15 and 50 mg progesterone from either Day 4 to Day 10 (E-P) or Day 4 to Day 15 (E+P). All ewes received 50 micrograms oestradiol-17 beta on Days 13, 14 and 15 and were hysterectomized on Day 16. In control ewes, endometrial ER mRNA, PR protein and OTR density were greater in E-P- than E+P- treated ewes. In E-P ewes, roIFN-tau decreased oestrogen-stimulated increases in ER and OTR, but not PR expression compared with control ewes. In E+P ewes, endometrial ER mRNA and protein, PR mRNA and protein, and OTR levels were lower in roIFN-tau-treated ewes than control ewes. Immunoreactive ER and PR were absent in the endometrial luminal and superficial glandular epithelium of roIFN-tau compared with control ewes, but were present in the deep glandular epithelium and stroma regardless of steroid or protein treatment. These results indicate that progesterone affects oestrogen-induced increases in endometrial ER, PR and OTR expression in the PR+ deep glandular epithelium and stroma, whereas IFN-tau suppresses oestrogen-induced increases ER, PR and OTR expression in the PR- luminal and superficial glandular epithelium. These combined actions of IFN-tau and progesterone to suppress oestrogen-induced increases in endometrial OTR formation would prevent pulsatile production of luteolytic prostaglandin F2 alpha by the endometrium during early pregnancy.
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PMID:Effects of interferon-tau and progesterone on oestrogen-stimulated expression of receptors for oestrogen, progesterone and oxytocin in the endometrium of ovariectomized ewes. 887 43

Oxytocin (OT) and its receptor (OTR) are synthesized in the endometrium and myometrium of the pregnant rat during late gestation. Both are regulated by estrogen and progesterone (P4), and tissue concentrations of both increase markedly before parturition. The P4 antagonist RU486 will induce parturition in the rat. The purpose of the present studies was to investigate changes in OT and OTR messenger RNA (mRNA) and peptide synthesis within the pregnant rat uterus during RU486-induced parturition. Pregnant rats were given a single injection of RU486 (2.5 mg/rat in oil) on day 15 of pregnancy (normal delivery occurs on day 22). Control animals received injections of oil only. Groups of animals (n = 5 in each group) were euthanized at 0, 6, 12, 24, and 48 h after injection and during labor (immediately after delivery of the first pup). Maternal serum estradiol (E2), P4 and uterine OT, and PGE2 concentrations were measured by RIA. Prostaglandin F2alpha and estrogen receptor levels were measured by enzyme immunoassay (EIA). OTR and P4 receptor (PR) were measured using radioligand-binding assays. OT, OTR, and estrogen receptor mRNAs were measured with ribonuclease protection assays. The average time to delivery, after RU486 injection, was 27.0 +/- 1.2 h. Serum E2 and P4 levels were increased slightly, but significantly, at 24 h after RU486. In controls, OT mRNA increased significantly, and this increase was blocked in the RU486 treatment group. OTR mRNA levels increased within 6 h of RU486 and remained elevated until delivery. OTR peptide was increased by 12 h. PGE2 and PGF2alpha were increased 3-fold and 16-fold, respectively, but not until after the increase in OTR had occurred. We conclude that the mechanism of action of RU486 is to inhibit the P4 suppression of OTR synthesis, allowing increased expression of OTR, which may directly stimulate myometrial contractions or act indirectly through increased synthesis of PGs.
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PMID:Effects of RU486 on estrogen, progesterone, oxytocin, and their receptors in the rat uterus during late gestation. 920 15

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

Developmental aspects of oxytocin (OT) receptors (OTR) in uterine tissues before puberty are not known. Bovine ovaries secrete some estradiol, but no progesterone, before puberty; the circulating levels of estradiol are between 1 and 3 pg/ml until puberty. Cross-bred Angus-Brahman heifers, in which puberty occurs around 12 months of age, were used to determine the concentrations of OTR from the late fetal stage to adulthood. PGF2alpha release in response to OT was determined in 3-, 6-, and 9-month-old heifers (n = 4 each). Myometrium, endometrium, and cervical mucosa were obtained from 3-week-old, 3-month-old, 6-month-old, and 9-month-old heifers and from adult cows at estrus. Whole uterus and cervix were taken from third trimester fetuses and at birth. [3H]OT binding and specificity, localization of immunoreactive (ir) OTR, OTR messenger RNA, and OT-induced release of PGF2alpha were determined. The uterus from fetuses and the neonate expressed OTR messenger RNA and bound [3H]OT. At 3 weeks of age, OTR concentrations per mg protein were very low, but at 3 months of age they had increased markedly in all three tissues. At 6 and 9 months of age, levels of OTR had risen further and were similar to those in adult cows at estrus. Prepubertal uterus also possessed separate vasopressin VP1 subtype receptors. The ir-OTR was localized in luminal epithelial cells of endometrium and cervical mucosa, most of which were ir positive, whereas in myometrium, clusters of ir-OTR-positive cells were found among large numbers of ir-OTR-negative cells. The PGF2alpha response to OT was insignificant in heifers of all age groups, in contrast to that in cows at estrus. Endometrial cells from 4- to 5-month-old heifers did not respond to OT with PG release in the absence or presence of added arachidonic acid. Tumor promoters, lipopolysaccharide, and interleukin-2 also failed to elicit PG release in vitro, although they induced PG release in similar cell cultures from cyclic cows. In summary, uterine tissues of prepubertal heifers have high levels of OTR, which appear to be developmentally regulated. These receptors are not coupled to PG synthase, or alternatively, the PG synthase gene is not expressed before puberty, possibly because the tissues have had no previous exposure to progesterone.
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PMID:Ontogeny of oxytocin receptors and oxytocin-induced stimulation of prostaglandin synthesis in prepubertal heifers. 960 82


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