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Gene Review

OXTR  -  oxytocin receptor

Homo sapiens

Synonyms: OT-R, Oxytocin receptor
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Disease relevance of OXTR


Psychiatry related information on OXTR


High impact information on OXTR


Chemical compound and disease context of OXTR


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


Associations of OXTR with chemical compounds


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


  1. Oxytocin synthesis and oxytocin receptor expression by cell lines of human small cell carcinoma of the lung stimulate tumor growth through autocrine/paracrine signaling. Péqueux, C., Breton, C., Hendrick, J.C., Hagelstein, M.T., Martens, H., Winkler, R., Geenen, V., Legros, J.J. Cancer Res. (2002) [Pubmed]
  2. Oxytocin receptor pattern of expression in primary lung cancer and in normal human lung. Péqueux, C., Breton, C., Hagelstein, M.T., Geenen, V., Legros, J.J. Lung Cancer (2005) [Pubmed]
  3. A plasmin-derived hexapeptide from the carboxyl end of osteocalcin counteracts oxytocin-mediated growth inhibition [corrected] of osteosarcoma cells. Novak, J.F., Judkins, M.B., Chernin, M.I., Cassoni, P., Bussolati, G., Nitche, J.A., Nishimoto, S.K. Cancer Res. (2000) [Pubmed]
  4. Investigation of the oxytocin receptor expression in human breast cancer tissue using newly established monoclonal antibodies. Ito, Y., Kobayashi, T., Kimura, T., Matsuura, N., Wakasugi, E., Takeda, T., Shimano, T., Kubota, Y., Nobunaga, T., Makino, Y., Azuma, C., Saji, F., Monden, M. Endocrinology (1996) [Pubmed]
  5. Oxytocin receptor expression in smooth muscle cells of peritoneal endometriotic lesions and ovarian endometriotic cysts. Mechsner, S., Bartley, J., Loddenkemper, C., Salomon, D.S., Starzinski-Powitz, A., Ebert, A.D. Fertil. Steril. (2005) [Pubmed]
  6. Oxytocin--a neuropeptide for affiliation: evidence from behavioral, receptor autoradiographic, and comparative studies. Insel, T.R. Psychoneuroendocrinology (1992) [Pubmed]
  7. Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Meaney, M.J. Annu. Rev. Neurosci. (2001) [Pubmed]
  8. Structure and expression of a human oxytocin receptor. Kimura, T., Tanizawa, O., Mori, K., Brownstein, M.J., Okayama, H. Nature (1992) [Pubmed]
  9. The effect of oxytocin receptor blockade on parturition in guinea pigs. Schellenberg, J.C. J. Clin. Invest. (1995) [Pubmed]
  10. Expression and localization of human oxytocin receptor mRNA and its protein in chorion and decidua during parturition. Takemura, M., Kimura, T., Nomura, S., Makino, Y., Inoue, T., Kikuchi, T., Kubota, Y., Tokugawa, Y., Nobunaga, T., Kamiura, S. J. Clin. Invest. (1994) [Pubmed]
  11. Estradiol and progesterone regulate oxytocin receptor binding and expression in human breast cancer cell lines. Amico, J.A., Rauk, P.N., Cai, H.M. Endocrine (2002) [Pubmed]
  12. Pharmacologic characterization of the oxytocin receptor in human uterine smooth muscle cells. Tahara, A., Tsukada, J., Tomura, Y., Wada, K., Kusayama, T., Ishii, N., Yatsu, T., Uchida, W., Tanaka, A. Br. J. Pharmacol. (2000) [Pubmed]
  13. Oxytocin modulates estrogen receptor alpha expression and function in MCF7 human breast cancer cells. Cassoni, P., Catalano, M.G., Sapino, A., Marrocco, T., Fazzari, A., Bussolati, G., Fortunati, N. Int. J. Oncol. (2002) [Pubmed]
  14. Evidence of oxytocin/oxytocin receptor interplay in human prostate gland and carcinomas. Cassoni, P., Marrocco, T., Sapino, A., Allia, E., Bussolati, G. Int. J. Oncol. (2004) [Pubmed]
  15. 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. Serradeil-Le Gal, C., Valette, G., Foulon, L., Germain, G., Advenier, C., Naline, E., Bardou, M., Martinolle, J.P., Pouzet, B., Raufaste, D., Garcia, C., Double-Cazanave, E., Pauly, M., Pascal, M., Barbier, A., Scatton, B., Maffrand, J.P., Le Fur, G. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  16. Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Wu, S., Jia, M., Ruan, Y., Liu, J., Guo, Y., Shuang, M., Gong, X., Zhang, Y., Yang, X., Zhang, D. Biol. Psychiatry (2005) [Pubmed]
  17. Phorbol ester treatment of human myometrial cells suppresses expression of oxytocin receptor through a mechanism that does not involve activator protein-1. Ball, A., Wang, J.W., Wong, S., Zielnik, B., Mitchell, J., Wang, N., Stemerman, M.B., Mitchell, B.F. Am. J. Physiol. Endocrinol. Metab. (2006) [Pubmed]
  18. Oxytocin receptor gene expression of estrogen-stimulated human myometrium in extracorporeally perfused non-pregnant uteri. Richter, O.N., Kübler, K., Schmolling, J., Kupka, M., Reinsberg, J., Ulrich, U., van der Ven, H., Wardelmann, E., van der Ven, K. Mol. Hum. Reprod. (2004) [Pubmed]
  19. Expression of oxytocin receptor in human pregnant myometrium. Kimura, T., Takemura, M., Nomura, S., Nobunaga, T., Kubota, Y., Inoue, T., Hashimoto, K., Kumazawa, I., Ito, Y., Ohashi, K., Koyama, M., Azuma, C., Kitamura, Y., Saji, F. Endocrinology (1996) [Pubmed]
  20. Dynamic interaction of human vasopressin/oxytocin receptor subtypes with G protein-coupled receptor kinases and protein kinase C after agonist stimulation. Berrada, K., Plesnicher, C.L., Luo, X., Thibonnier, M. J. Biol. Chem. (2000) [Pubmed]
  21. Extracellular signal-regulated kinase 1/2 activation by myometrial oxytocin receptor involves Galpha(q)Gbetagamma and epidermal growth factor receptor tyrosine kinase activation. Zhong, M., Yang, M., Sanborn, B.M. Endocrinology (2003) [Pubmed]
  22. Design of peptide oxytocin antagonists with strikingly higher affinities and selectivities for the human oxytocin receptor than atosiban. Manning, M., Cheng, L.L., Stoev, S., Wo, N.C., Chan, W.Y., Szeto, H.H., Durroux, T., Mouillac, B., Barberis, C. J. Pept. Sci. (2005) [Pubmed]
  23. Molecular modeling of the oxytocin receptor/bioligand interactions. Politowska, E., Czaplewski, C., Ciarkowski, J. Acta Biochim. Pol. (1999) [Pubmed]
  24. Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-beta-arrestin complexes after receptor endocytosis*. Oakley, R.H., Laporte, S.A., Holt, J.A., Barak, L.S., Caron, M.G. J. Biol. Chem. (2001) [Pubmed]
  25. The DRY motif as a molecular switch of the human oxytocin receptor. Favre, N., Fanelli, F., Missotten, M., Nichols, A., Wilson, J., di Tiani, M., Rommel, C., Scheer, A. Biochemistry (2005) [Pubmed]
  26. Transcriptional regulation of oxytocin receptor by interleukin-1beta and interleukin-6. Schmid, B., Wong, S., Mitchell, B.F. Endocrinology (2001) [Pubmed]
  27. Oxytocin stimulates the translocation of oxytocinase of human vascular endothelial cells via activation of oxytocin receptors. Nakamura, H., Itakuara, A., Okamura, M., Ito, M., Iwase, A., Nakanishi, Y., Okada, M., Nagasaka, T., Mizutani, S. Endocrinology (2000) [Pubmed]
  28. Upregulations of Gata4 and oxytocin receptor are important in cardiomyocyte differentiation processes of P19CL6 cells. Uchida, S., Fuke, S., Tsukahara, T. J. Cell. Biochem. (2007) [Pubmed]
  29. Molecular mechanisms regulating the effects of oxytocin on myometrial intracellular calcium. Sanborn, B.M., Dodge, K., Monga, M., Qian, A., Wang, W., Yue, C. Adv. Exp. Med. Biol. (1998) [Pubmed]
  30. The effect of relaxin on the oxytocin receptor in human uterine smooth muscle cells. Friebe-Hoffmann, U., Baston, D.M., Chiao, J.P., Winebrenner, L.D., Krüssel, J.S., Hoffmann, T.K., Hirchenhain, J., Rauk, P.N. Regul. Pept. (2007) [Pubmed]
  31. Cigarette smoke extract enhances oxytocin-induced rhythmic contractions of rat and human preterm myometrium. Nakamoto, T., Yasuda, K., Yasuhara, M., Nakajima, T., Mizokami, T., Okada, H., Kanzaki, H. Reproduction (2006) [Pubmed]
  32. Interleukin-1-induced NF-{kappa}B recruitment to the oxytocin receptor gene inhibits RNA polymerase II-promoter interactions in cultured human myometrial cells. Soloff, M.S., Izban, M.G., Cook, D.L., Jeng, Y.J., Mifflin, R.C. Mol. Hum. Reprod. (2006) [Pubmed]
  33. Internalization and desensitization of the oxytocin receptor is inhibited by Dynamin and clathrin mutants in human embryonic kidney 293 cells. Smith, M.P., Ayad, V.J., Mundell, S.J., McArdle, C.A., Kelly, E., López Bernal, A. Mol. Endocrinol. (2006) [Pubmed]
  34. Molecular modeling of interactions of the non-peptide antagonist YM087 with the human vasopressin V1a, V2 receptors and with oxytocin receptors. Giełdoń, A., Kaźmierkiewicz, R., Slusarz, R., Ciarkowski, J. J. Comput. Aided Mol. Des. (2001) [Pubmed]
  35. Molecular pharmacology and modeling of vasopressin receptors. Thibonnier, M., Coles, P., Thibonnier, A., Shoham, M. Prog. Brain Res. (2002) [Pubmed]
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