Download PDF
Semin Reprod Med 2007; 25(1): 052-059
DOI: 10.1055/s-2006-956775
Copyright © 2007 by Thieme Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Regulation of Oxytocin Receptors and Oxytocin Receptor Signaling

Andrew M. Blanks1 , Anatoly Shmygol1 , Steven Thornton1
  • 1Warwick Medical School, Clinical Sciences Research Institute, University Hospital of Coventry and Warwickshire, Coventry, United Kingdom
Further Information

Publication History

Publication Date:
05 January 2007 (online)

    Permissions and Reprints

ABSTRACT

The oxytocin (OT) -oxytocin receptor (OTR) system plays a key role in many aspects of mammalian reproduction as well as several other physiological processes such as bond pairing and cardiovascular homeostasis. To manifest these diverse physiological roles, the transcription and expression of the OTR is tightly regulated within reproductive, cardiovascular, and neuronal tissues. The expression of the OTR within the mammalian uterus is regulated during gestation with a peak at the day of delivery. The control of this dramatic increase in expression is mediated in rodent species by a combination of stretch, classical steroid hormone stimulation, and repression. In the human uterus events are less clear, although a prominent role for inflammatory-related rapid-response genes and novel transcription factors such as hMafF (human homologue of chicken musculoaponeurotic fibrosarcoma oncogene family protein F) have been put forward. In the uterus the potent uterotonic actions of OT are mediated by the OTR through G-protein activation to stimulate phospholipase C activity. The activated OTR increases contraction frequency and increases force by sensitizing the contractile apparatus of the myocytes to calcium. This review summarizes the current knowledge of the complex regulation of OTR transcription in the myometrium and the intracellular signaling mechanisms through which OT mediates its potent stimulatory effects.

KEYWORDS

Oxytocin - oxytocin receptor - myometrium - parturition - uterus

REFERENCES

  • 1 Bielsky I F, Young L J. Oxytocin, vasopressin, and social recognition in mammals.  Peptides. 2004;  25 1565-1574
    CrossrefPubMedGoogle Scholar
  • 2 Cassoni P, Sapino A, Marrocco T, Chini B, Bussolati G. Oxytocin and oxytocin receptors in cancer cells and proliferation.  J Neuroendocrinol. 2004;  16 362-364
    CrossrefPubMedGoogle Scholar
  • 3 Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation.  Physiol Rev. 2001;  81 629-683
    CrossrefPubMedGoogle Scholar
  • 4 Blanks A M, Thornton S. The role of oxytocin in parturition.  BJOG. 2003;  110(suppl 20) 46-51
    PubMedGoogle Scholar
  • 5 McCann S M, Antunes-Rodrigues J, Jankowski M, Gutkowska J. Oxytocin, vasopressin and atrial natriuretic peptide control body fluid homeostasis by action on their receptors in brain, cardiovascular system and kidney.  Prog Brain Res. 2002;  139 309-328
    PubMedGoogle Scholar
  • 6 Lipschitz D L, Crowley W R, Armstrong W E, Bealer S L. Neurochemical bases of plasticity in the magnocellular oxytocin system during gestation.  Exp Neurol. 2005;  196 210-223
    CrossrefPubMedGoogle Scholar
  • 7 Fuchs A R, Fuchs F, Husslein P, Soloff M S. Oxytocin receptors in the human uterus during pregnancy and parturition.  Am J Obstet Gynecol. 1984;  150 734-741
    PubMedGoogle Scholar
  • 8 Kimura T, Tanizawa O, Mori K, Brownstein M J, Okayama H. Structure and expression of a human oxytocin receptor.  Nature. 1992;  356 526-529
    PubMedGoogle Scholar
  • 9 Kimura T. Investigation of the oxytocin receptor at the molecular level.  Adv Exp Med Biol. 1995;  395 259-268
    PubMedGoogle Scholar
  • 10 Copland J A, Ives K L, Simmons D J, Soloff M S. Functional oxytocin receptors discovered in human osteoblasts.  Endocrinology. 1999;  140 4371-4374
    CrossrefPubMedGoogle Scholar
  • 11 Thibonnier M, Conarty D M, Preston J A et al.. Human vascular endothelial cells express oxytocin receptors.  Endocrinology. 1999;  140 1301-1309
    PubMedGoogle Scholar
  • 12 Inoue T, Kimura T, Azuma C et al.. Structural organization of the human oxytocin receptor gene.  J Biol Chem. 1994;  269 32451-32456
    PubMedGoogle Scholar
  • 13 Simmons Jr C F, Clancy T E, Quan R, Knoll J H. The oxytocin receptor gene (OXTR) localizes to human chromosome 3p25 by fluorescence in situ hybridization and PCR analysis of somatic cell hybrids.  Genomics. 1995;  26 623-625
    CrossrefPubMedGoogle Scholar
  • 14 Murasawa S, Matsubara H, Kijima K et al.. Structure of the rat V1a vasopressin receptor gene and characterization of its promoter region and complete cDNA sequence of the 3′-end.  J Biol Chem. 1995;  270 20042-20050
    CrossrefPubMedGoogle Scholar
  • 15 Terzidou V, Lee Y, Lindstrom T et al.. Regulation of the human oxytocin receptor by nuclear factor-kappaB and CCAAT/enhancer-binding protein-beta.  J Clin Endocrinol Metab. 2006;  91 2317-2326
    CrossrefPubMedGoogle Scholar
  • 16 Kubota Y, Kimura T, Hashimoto K et al.. Structure and expression of the mouse oxytocin receptor gene.  Mol Cell Endocrinol. 1996;  124 25-32
    CrossrefPubMedGoogle Scholar
  • 17 Bale T L, Dorsa D M. Cloning, novel promoter sequence, and estrogen regulation of a rat oxytocin receptor gene.  Endocrinology. 1997;  138 1151-1158
    CrossrefPubMedGoogle Scholar
  • 18 Larcher A, Neculcea J, Breton C et al.. Oxytocin receptor gene expression in the rat uterus during pregnancy and the estrous cycle and in response to gonadal steroid treatment.  Endocrinology. 1995;  136 5350-5356
    CrossrefPubMedGoogle Scholar
  • 19 Fuchs A R, Periyasamy S, Alexandrova M, Soloff M S. Correlation between oxytocin receptor concentration and responsiveness to oxytocin in pregnant rat myometrium: effects of ovarian steroids.  Endocrinology. 1983;  113 742-749
    PubMedGoogle Scholar
  • 20 Fang X, Wong S, Mitchell B F. Relationships among sex steroids, oxytocin, and their receptors in the rat uterus during late gestation and at parturition.  Endocrinology. 1996;  137 3213-3219
    CrossrefPubMedGoogle Scholar
  • 21 Fang X, Wong S, Mitchell B F. Effects of RU486 on estrogen, progesterone, oxytocin, and their receptors in the rat uterus during late gestation.  Endocrinology. 1997;  138 2763-2768
    CrossrefPubMedGoogle Scholar
  • 22 Young L J, Wang Z, Donaldson R, Rissman E F. Estrogen receptor alpha is essential for induction of oxytocin receptor by estrogen.  Neuroreport. 1998;  9 933-936
    PubMedGoogle Scholar
  • 23 Parry L J, Bathgate R A, Shaw G, Renfree M B, Ivell R. Evidence for a local fetal influence on myometrial oxytocin receptors during pregnancy in the tammar wallaby (Macropus eugenii).  Biol Reprod. 1997;  56 200-207
    CrossrefPubMedGoogle Scholar
  • 24 Ou C W, Orsino A, Lye S J. Expression of connexin-43 and connexin-26 in the rat myometrium during pregnancy and labor is differentially regulated by mechanical and hormonal signals.  Endocrinology. 1997;  138 5398-5407
    CrossrefPubMedGoogle Scholar
  • 25 Terzidou V, Sooranna S R, Kim L U et al.. Mechanical stretch up-regulates the human oxytocin receptor in primary human uterine myocytes.  J Clin Endocrinol Metab. 2005;  90 237-246
    CrossrefPubMedGoogle Scholar
  • 26 Bale T L, Dorsa D M. Transcriptional regulation of the oxytocin receptor gene.  Adv Exp Med Biol. 1998;  449 307-315
    PubMedGoogle Scholar
  • 27 Hoare S, Copland J A, Wood I G et al.. Identification of a GABP alpha/beta binding site involved in the induction of oxytocin receptor gene expression in human breast cells, potentiation by c-Fos/c-Jun.  Endocrinology. 1999;  140 2268-2279
    CrossrefPubMedGoogle Scholar
  • 28 Lye S J, Mitchell J, Nashman N et al.. Role of mechanical signals in the onset of term and preterm labor.  Front Horm Res. 2001;  27 165-178
    PubMedGoogle Scholar
  • 29 Metz R, Ziff E. cAMP stimulates the C/EBP-related transcription factor rNFIL-6 to trans-locate to the nucleus and induce c-fos transcription.  Genes Dev. 1991;  5 1754-1766
    PubMedGoogle Scholar
  • 30 Inoue H, Yokoyama C, Hara S, Tone Y, Tanabe T. Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular endothelial cells. Involvement of both nuclear factor for interleukin-6 expression site and cAMP response element.  J Biol Chem. 1995;  270 24965-24971
    CrossrefPubMedGoogle Scholar
  • 31 Akira S, Kishimoto T. NF-IL6 and NF-kappa B in cytokine gene regulation.  Adv Immunol. 1997;  65 1-46
    PubMedGoogle Scholar
  • 32 Romero R, Avila C, Brekus C A, Morotti R. The role of systemic and intrauterine infection in preterm parturition.  Ann N Y Acad Sci. 1991;  622 355-375
    CrossrefPubMedGoogle Scholar
  • 33 Dudley D J, Hunter C, Mitchell M D, Varner M W. Clinical value of amniotic fluid interleukin-6 determinations in the management of preterm labour.  Br J Obstet Gynaecol. 1994;  101 592-597
    PubMedGoogle Scholar
  • 34 Schmid B, Wong S, Mitchell B F. Transcriptional regulation of oxytocin receptor by interleukin-1beta and interleukin-6.  Endocrinology. 2001;  142 1380-1385
    CrossrefPubMedGoogle Scholar
  • 35 Nelson D E, Ihekwaba A E, Elliot M et al.. Oscillations in NF-kappaB signaling control the dynamics of gene expression.  Science. 2004;  306 704-708
    CrossrefPubMedGoogle Scholar
  • 36 Kimura T, Mizumoto Y, Ivell R. Differential protein-DNA binding analysis identifies a novel enhancer element, US-1, involved in the upregulation of the oxytocin receptor gene in human myometrium at term.  Mol Cell Endocrinol. 1999;  148 137-149
    CrossrefPubMedGoogle Scholar
  • 37 Kimura T, Ivell R, Rust W et al.. Molecular cloning of a human MafF homologue, which specifically binds to the oxytocin receptor gene in term myometrium.  Biochem Biophys Res Commun. 1999;  264 86-92
    CrossrefPubMedGoogle Scholar
  • 38 Bethin K E, Nagai Y, Sladek R et al.. Microarray analysis of uterine gene expression in mouse and human pregnancy.  Mol Endocrinol. 2003;  17 1454-1469
    CrossrefPubMedGoogle Scholar
  • 39 Massrieh W, Derjuga A, Doualla-Bell F et al.. Regulation of the MAFF transcription factor by proinflammatory cytokines in myometrial cells.  Biol Reprod. 2006;  74 699-705
    CrossrefPubMedGoogle Scholar
  • 40 Ye X, Li Y, Huang Q et al.. The novel human gene MIP functions as a co-activator of hMafF.  Arch Biochem Biophys. 2006;  449 87-93
    CrossrefPubMedGoogle Scholar
  • 41 Ivell R, Bathgate R A, Walther N, Kimura T. The molecular basis of oxytocin and oxytocin receptor gene expression in reproductive tissues.  Adv Exp Med Biol. 1998;  449 297-306
    PubMedGoogle Scholar
  • 42 Mizumoto Y, Kimura T, Ivell R. A genomic element within the third intron of the human oxytocin receptor gene may be involved in transcriptional suppression.  Mol Cell Endocrinol. 1997;  135 129-138
    CrossrefPubMedGoogle Scholar
  • 43 Qian A, Wang W, Sanborn B M. Evidence for the involvement of several intracellular domains in the coupling of oxytocin receptor to G alpha(q/11).  Cell Signal. 1998;  10 101-105
    CrossrefPubMedGoogle Scholar
  • 44 Sanborn B M, Dodge K, Monga M et al.. Molecular mechanisms regulating the effects of oxytocin on myometrial intracellular calcium.  Adv Exp Med Biol. 1998;  449 277-286
    PubMedGoogle Scholar
  • 45 Hoare S, Copland J A, Strakova Z et al.. 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.  J Biol Chem. 1999;  274 28682-28689
    CrossrefPubMedGoogle Scholar
  • 46 Ku C Y, Qian A, Wen Y, Anwer K, Sanborn B M. Oxytocin stimulates myometrial guanosine triphosphatase and phospholipase-C activities via coupling to G alpha q/11.  Endocrinology. 1995;  136 1509-1515
    CrossrefPubMedGoogle Scholar
  • 47 Arnaudeau S, Lepretre N, Mironneau J. Oxytocin mobilizes calcium from a unique heparin-sensitive and thapsigargin-sensitive store in single myometrial cells from pregnant rats.  Pflugers Arch. 1994;  428 51-59
    PubMedGoogle Scholar
  • 48 Phaneuf S, Carrasco M P, Europe-Finner G N, Hamilton C H, Lopez Bernal A. Multiple G proteins and phospholipase C isoforms in human myometrial cells: implication for oxytocin action.  J Clin Endocrinol Metab. 1996;  81 2098-2103
    CrossrefPubMedGoogle Scholar
  • 49 Berridge M J, Irvine R F. Inositol trisphosphate, a novel second messenger in cellular signal transduction.  Nature. 1984;  312 315-321
    CrossrefPubMedGoogle Scholar
  • 50 Word R A, Stull J T, Casey M L, Kamm K E. Contractile elements and myosin light chain phosphorylation in myometrial tissue from nonpregnant and pregnant women.  J Clin Invest. 1993;  92 29-37
    PubMedGoogle Scholar
  • 51 Oancea E, Meyer T. Protein kinase C as a molecular machine for decoding calcium and diacylglycerol signals.  Cell. 1998;  95 307-318
    CrossrefPubMedGoogle Scholar
  • 52 Carrasco M P, Phaneuf S, Asboth G, Lopez Bernal A. Fluprostenol activates phospholipase C and Ca2 + mobilization in human myometrial cells.  J Clin Endocrinol Metab. 1996;  81 2104-2110
    CrossrefPubMedGoogle Scholar
  • 53 Khac L D, Arnaudeau S, Lepretre N, Mironneau J, Harbon S. Beta adrenergic receptor activation attenuates the generation of inositol phosphates in the pregnant rat myometrium. Correlation with inhibition of Ca + + influx, a cAMP-independent mechanism.  J Pharmacol Exp Ther. 1996;  276 130-136
    PubMedGoogle Scholar
  • 54 Molnar M, Rigo Jr J, Hertelendy F. Signal transduction in human myometrial cells.  Acta Physiol Hung. 1996;  84 89-97
    PubMedGoogle Scholar
  • 55 Baek K J, Kwon N S, Lee H S et al.. Oxytocin receptor couples to the 80 kDa Gh alpha family protein in human myometrium.  Biochem J. 1996;  315(pt 3) 739-744
    PubMedGoogle Scholar
  • 56 Park E S, Won J H, Han K J et al.. Phospholipase C-delta1 and oxytocin receptor signalling: evidence of its role as an effector.  Biochem J. 1998;  331(pt 1) 283-289
    PubMedGoogle Scholar
  • 57 Shmygol A, Gullam J, Blanks A, Thornton S. Multiple mechanisms involved in oxytocin-induced modulation of myometrial contractility.  Acta Pharmacol Sin. 2006;  27 827-832
    CrossrefPubMedGoogle Scholar
  • 58 Parkington H C, Tonta M A, Davies N K, Brennecke S P, Coleman H A. Hyperpolarization and slowing of the rate of contraction in human uterus in pregnancy by prostaglandins E2 and f2alpha: involvement of the Na + pump.  J Physiol. 1999;  514(pt 1) 229-243
    CrossrefPubMedGoogle Scholar
  • 59 Arnaudeau S, Lepretre N, Mironneau J. Chloride and monovalent ion-selective cation currents activated by oxytocin in pregnant rat myometrial cells.  Am J Obstet Gynecol. 1994;  171 491-501
    PubMedGoogle Scholar
  • 60 Mironneau J. Ion channels and the control of uterine contractility. In: Control of Uterine Contractility. Garfield RE, Tabb TN Boca Raton, FL; CRC Press 1994: 1-20
  • 61 Nakao K, Inoue Y, Okabe K, Kawarabayashi T, Kitamura K. Oxytocin enhances action potentials in pregnant human myometrium-a study with microelectrodes.  Am J Obstet Gynecol. 1997;  177 222-228
    CrossrefPubMedGoogle Scholar
  • 62 Kawarabayashi T, Kishikawa T, Sugimori H. Effect of oxytocin on spontaneous electrical and mechanical activities in pregnant human myometrium.  Am J Obstet Gynecol. 1986;  155 671-676
    PubMedGoogle Scholar
  • 63 McKillen K, Thornton S, Taylor C W. Oxytocin increases the [Ca2 + ]i sensitivity of human myometrium during the falling phase of phasic contractions.  Am J Physiol. 1999;  276 E345-E351
    PubMedGoogle Scholar
  • 64 Somlyo A P, Somlyo A V. Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II.  J Physiol. 2000;  522(Pt 2) 177-185
    CrossrefPubMedGoogle Scholar
  • 65 Kimura K, Ito M, Amano H et al.. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase).  Science. 1996;  273 245-248
    PubMedGoogle Scholar
  • 66 Katoh H, Aoki J, Yamaguchi Y et al.. Constitutively active Galpha12, Galpha13, and Galphaq induce Rho-dependent neurite retraction through different signaling pathways.  J Biol Chem. 1998;  273 28700-28707
    CrossrefPubMedGoogle Scholar
  • 67 Moore F, Da Silva C, Wilde J I et al.. Up-regulation of p21- and RhoA-activated protein kinases in human pregnant myometrium.  Biochem Biophys Res Commun. 2000;  269 322-326
    CrossrefPubMedGoogle Scholar
  • 68 Kupittayanant S, Burdyga T, Wray S. The effects of inhibiting Rho-associated kinase with Y-27632 on force and intracellular calcium in human myometrium.  Pflugers Arch. 2001;  443 112-114
    PubMedGoogle Scholar
  • 69 Woodcock N A, Taylor C W, Thornton S. Effect of an oxytocin receptor antagonist and rho kinase inhibitor on the [Ca + + ]i sensitivity of human myometrium.  Am J Obstet Gynecol. 2004;  190 222-228
    CrossrefPubMedGoogle Scholar
  • 70 Kitazawa T, Eto M, Woodsome T P, Brautigan D L. Agonists trigger G protein-mediated activation of the CPI-17 inhibitor phosphoprotein of myosin light chain phosphatase to enhance vascular smooth muscle contractility.  J Biol Chem. 2000;  275 9897-9900
    CrossrefPubMedGoogle Scholar
  • 71 Koyama M, Ito M, Feng J et al.. Phosphorylation of CPI-17, an inhibitory phosphoprotein of smooth muscle myosin phosphatase, by Rho-kinase.  FEBS Lett. 2000;  475 197-200
    CrossrefPubMedGoogle Scholar
  • 72 Gong M C, Kinter M T, Somlyo A V, Somlyo A P. Arachidonic acid and diacylglycerol release associated with inhibition of myosin light chain dephosphorylation in rabbit smooth muscle.  J Physiol. 1995;  486(pt 1) 113-122
    PubMedGoogle Scholar

 Dr.
Andrew M Blanks

RCUK Fellow in Reproduction, Warwick Medical School, Clinical Sciences Research Institute, University Hospital of Coventry and Warwickshire

Clifford Bridge Road, Coventry CV2 2DX, United Kingdom

Email: Andrew.Blanks@warwick.ac.uk