Disease relevance of OXTR

• Oxytocin synthesis and oxytocin receptor expression by cell lines of human small cell carcinoma of the lung stimulate tumor growth through autocrine/paracrine signaling [1].
• Oxytocin receptor pattern of expression in primary lung cancer and in normal human lung [2].
• Because the sequence of OC-derived hexapeptide (HP) is nearly identical to the E2 region of the oxytocin receptor (OTR), we set out to ascertain whether the HP interferes with the osteosarcoma (OS)-associated oxytocin (OT) system [3].
• Investigation of the oxytocin receptor expression in human breast cancer tissue using newly established monoclonal antibodies [4].
• MAIN OUTCOME MEASURE(S): Comparison of the immunoreactive score of the OTR and smooth muscle actin expression with the smooth muscle content in peritoneum with and without endometriosis [5].

Psychiatry related information on OXTR

• A model for OT's effects on social behavior is proposed, which relies on the heterologous regulation of the brain OT receptor [6].
• Maternal care also influences the maternal behavior of female offspring, an effect that appears to be related to oxytocin receptor gene expression, and which forms the basis for the intergenerational transmission of individual differences in stress reactivity [7].

High impact information on OXTR

• The oxytocin receptor, expressed in Xenopus oocytes, specifically responds to oxytocin and induces an inward membrane current [8].
• The effect of oxytocin receptor blockade on parturition in guinea pigs [9].
• OTR gene expression in chorio-decidual tissue increased fivefold during the course of parturition [10].
• We demonstrated the enhanced expression of OT receptor (OTR) mRNA in chorio-decidual tissue, using the polymerase chain reaction after the reverse transcriptase reaction (RT-PCR) and Northern blot analysis [10].
• In situ hybridization of fetal membrane revealed the expression of OTR mRNA in maternally derived decidual cells [10].

Chemical compound and disease context of OXTR

• Estradiol and progesterone regulate oxytocin receptor binding and expression in human breast cancer cell lines [11].
• The oxytocin receptor antagonists, atosiban and L-371257, potently and concentration-dependently inhibited oxytocin-induced [Ca(2+)](i) increase and hyperplasia [12].
• Oxytocin (OT) inhibits the proliferation of MCF7 estrogen-dependent human breast cancer cells, via specific OT receptors (OTR) [13].
• In order to determine whether OTR might mediate a biological effect of oxytocin (OT) in prostate cancer cells, OTR expression was studied by RT-PCR and immunofluorescence technique in the human androgen-independent prostate cancer cell line DU145 [14].
• SSR126768A (4-chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide, hydrochloride): a new selective and orally active oxytocin receptor antagonist for the prevention of preterm labor [15].

Biological context of OXTR

• Animal models and linkage data from genome screens indicate that the oxytocin receptor gene (OXTR) is an excellent candidate for research concerning psychiatric disorders, particularly those involving social impairments, such as autism [16].
• METHODS: We genotyped four single nucleotide polymorphisms (SNPs) located within the OXTR gene of 195 Chinese Han autism trios, using polymerase chain reaction-restriction fragment length polymorphism analysis [16].
• Diminished PKC activity in late pregnancy could underlie the increased expression of uterine OTR preceding labor onset [17].
• Gene expression of the myometrial OTR in both groups was compared using reverse transcriptase triple primer PCR [18].
• However, maximum OTR levels of the uterine fundus in group B did not reach concentrations of specimens of third trimester of pregnancy which were used as positive controls [18].

Anatomical context of OXTR

• Expression of oxytocin receptor in human pregnant myometrium [19].
• Some of the smooth muscle cells were expressed high levels of the receptor at the messenger RNA and protein level, and they were surrounded with cells weakly positive for the OTR or negative [19].
• Using cell cultures of transformed human uterine myocytes, we determined the effects of PKC agonists and antagonists on the expression of OTR [17].
• Oxytocin receptor gene expression of estrogen-stimulated human myometrium in extracorporeally perfused non-pregnant uteri [18].
• Herein, we observe, in normal human lung, that OTR is colocalized with vascular endothelial cells of the lung and is not expressed by lung cells of epithelial nature [2].

Associations of OXTR with chemical compounds

• Dynamic interaction of human vasopressin/oxytocin receptor subtypes with G protein-coupled receptor kinases and protein kinase C after agonist stimulation [20].
• Extracellular signal-regulated kinase 1/2 activation by myometrial oxytocin receptor involves Galpha(q)Gbetagamma and epidermal growth factor receptor tyrosine kinase activation [21].
• Peptides 1-4 and B exhibit respectively 449, 263, 1091, 546 and 129 times greater affinity for the hOTR than atosiban (K(i) = 76.4 nM) [22].
• Subsequently, the OTR complexes with a selective agonist [Thr4,Gly7]OT, a selective cyclohexapeptide antagonist L-366,948 and oxytocin itself were modeled and relaxed using a constrained simulated annealing (CSA) protocol [23].
• We show in real time and in live human embryonic kidney (HEK-293) cells that a beta-arrestin-2-green fluorescent protein conjugate internalizes into endocytic vesicles with agonist-activated neurotensin-1 receptor, oxytocin receptor, angiotensin II type 1A receptor, and substance P receptor [24].

Physical interactions of OXTR

• Molecular simulations of the free and OT-bound forms of wild-type OTR and of the D136(3.49)N constitutively active mutant suggest that the receptor portions close to the E/DRY and NPxxY motifs are particularly susceptible to undergoing structural modification in response to activating mutations and agonist binding [25].
• The 5'-flanking region of the human OT receptor gene contains several putative binding sites for nuclear factor-interleukin-6 (NF-IL6), also known as CAAT/enhancer binding protein-beta [26].
• 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 [27].
• The in silico analysis of the upstream sequence of the oxytocin receptor predicted putative binding sites for Gata4 and Nkx2 [28].
• Several lines of evidence indicate that the oxytocin receptor is functionally coupled to GTP-binding proteins of the G alpha q/11 class which stimulate phospholipase C activity [29].

Regulatory relationships of OXTR

• Oxytocin receptor mRNA and protein expression were down regulated by RLX about 50% and 35% respectively [30].
• These findings suggest that CSE directly increases the contractile sensitivity of preterm myometrium in response to OT by upregulating the expression of OTR mRNA and thereby increases the risk of preterm delivery in women, who smoke during pregnancy [31].
• Interleukin-1-induced NF-{kappa}B recruitment to the oxytocin receptor gene inhibits RNA polymerase II-promoter interactions in cultured human myometrial cells [32].
• Internalization and desensitization of the oxytocin receptor is inhibited by Dynamin and clathrin mutants in human embryonic kidney 293 cells [33].
• Using deletion analysis and functional transfection studies in HeLa cells, we demonstrated that the OT receptor gene promoter displays constitutive basal activity and is negatively regulated by both IL-1beta and IL-6 [26].

Other interactions of OXTR

• [3H]Thymidine incorporations, applied on H345 cells, demonstrated a dose-dependent mitogenic effect of exogenous OT (1 and 100 nM) that was abolished by the OTR antagonist OVTA [1].
• YM087 was computer-docked to V1aR, V2R and OTR using the AutoDock (Olson et al., Scripps Research Institute, La Jolla, USA) and subsequently relaxed using restrained simulated annealing and molecular dynamics, as implemented in AMBER program (Kollman et al., University of California, San Francisco, USA) [34].
• Conclusion: We report for the first time an effect of RLX on OTR regulation in human uterine myometrial cells [30].
• NOTE TO THE READER: The recent cloning and molecular characterization of AVP/OT receptor subtypes call for the revision of their nomenclature [35].
• Phorbol ester treatment of human myometrial cells suppresses expression of oxytocin receptor through a mechanism that does not involve activator protein-1 [17].

Analytical, diagnostic and therapeutic context of OXTR

• We examined the localization and expression of the OTR in human myometrium by means of in situ hybridization, immunohistochemistry, and Northern and Western blotting [19].
• The effects on OTR binding, mRNA and protein expression were evaluated by means of (125)I-OVT binding assay, RT-PCR and flow cytometry [30].
• Peptides 1-8 were evaluated for agonistic and antagonistic activities in in vitro and in vivo rat bioassays, in rat OT receptor (rOTR) binding assays and in human OT receptor (hOTR) and human vasopressin (VP) vasopressor (V(1a)) receptor (hV(1a)R) binding assays [22].
• The expression levels of rat OTR mRNA in the CSE (10(-7) pieces/ml) group were significantly higher than in the control group (P < 0.01) [31].
• Using a technique combining multiple sequence alignments with available experimental constraints, a reliable OTR model was built [23].

References