Skip to main content

Molecular Mechanisms Regulating the Effects of Oxytocin on Myometrial Intracellular Calcium

  • Chapter
Vasopressin and Oxytocin

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 449))

Abstract

Oxytocin stimulates an increase in intracellular calcium in uterine myometrium by several mechanisms. Several lines of evidence indicate that the oxytocin receptor is functionally coupled to GTP-binding proteins of the Gαq/11 class which stimulate phospholipase C activity. The IP3 generated as a result of phospholipase C activation can trigger release of calcium from intracellular stores. The finding that the oxytocin-stimulated increase in intracellular calcium in myometrial cells is greater in the presence of extracellular calcium than that in its absence indicates that oxytocin also has effects on calcium entry. This action is nifedipine-insensitive but may involve indirect stimulation of calcium entry through release-operated channels.

An anti-Gαq/11 antibody inhibits both oxytocin-stimulated GTPase activity and phospholipase C activity in myometrial membranes. The stimulation by oxytocin of phosphoinositide turnover in COS cells transfected with a plasmid expressing the oxytocin receptor is enhanced by cotransfection of Gαq. Co-transfection of intracellular domains of the oxytocin receptor causes varying degrees of interference with oxytocin-stimulated phosphoinositide turnover. The data suggest that more than one intracellular domain is involved in oxytocin receptor/G-protein coupling.

Oxytocin receptor stimulation of phospholipase C is inhibited by cAMP. This occurs in myometrial cells and in COS cells transfected with a plasmid expressing the receptor. The inhibitory mechanism involves the action of protein kinase A and is probably targeted indirectly at the Gαq/11 /phospholipase C coupling step.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

eBook
USD 16.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Sanborn BM, Anwer K, Monga M, Stefani E, Toro L, Singh SP 1994 Modification of Ca“ regulatory systems. In: Garfield RE, Tabb TB (eds) Control of Uterine Contractility. CRC Press, Boca Raton FL, pp. 105–128

    Google Scholar 

  2. Word RA, Stull JT, Kamm KE, Casey ML Regulation of smooth-muscle contractility: Ca“ and myosin phosphorylation. In: Garfield RE (ed) Uterine Contractility. Serono Symposium USA, Norwell MA, pp. 43–52

    Google Scholar 

  3. Sanborn BM, Anwer K Hormonal regulation of myometrial intracellular calcium. In: Garfield RE (ed) Uterine Contractility. Serono Symposium USA, Norwell MA, pp. 69–82

    Google Scholar 

  4. Rhee SG, Choi KD 1992 Regulation of inositol phospholipid-specific phospholipase C isozymes. J Biol Chem:12393–12396

    Google Scholar 

  5. Hepler JR, Gilman AG 1992 G Proteins. Trends in Biochem Sci 17:383–387

    Article  CAS  Google Scholar 

  6. Hedin KE, Duerson K, Clapham DE 1993 Specificity of receptor-G protein interactions: Searching for the structure behind the signal. Cellular Signaling 5:505–518

    Article  CAS  Google Scholar 

  7. Sanborn BM 1995 Ion channels and the control of myometrial electrical activity. Sem Perinatol 19:31–40

    Article  CAS  Google Scholar 

  8. Berridge MJ 1995 Capacitative calcium entry. Biochem J 312:1–11

    PubMed  CAS  Google Scholar 

  9. Putney JW Jr 1997 Type 3 inositol 1,4,5-trisphosphate receptor and capacitative calcium entry. Cell Calcium 21:257–261

    Article  PubMed  CAS  Google Scholar 

  10. Birnbaumer L, Zhu X, Jiang M, Boulay G, Peyton M, Vannier B, Brown D, Platano D, Sadeght H, Stefani E, Birnbaumer M 1996 On the molecular basis and regulation of cellular capacitative calcium entry: roles for Trp proteins. Proc Natl Acad Sci USA 93:15195–15202

    Article  PubMed  CAS  Google Scholar 

  11. Smrka A, Sternweis PC 1993 Regulation of purified subtypes of phosphatidylinositol-specific phospholipase Cß by G protein a and 13y subunits. J Biol Chem 268:9667–9674

    Google Scholar 

  12. Kimura T, Tanizawa O, Mori K, Brownstein MJ, Okayama H 1992 Structure and expression of a human oxytocin receptor. Nature 356:526–529

    Article  PubMed  CAS  Google Scholar 

  13. Anwer K, Monga M, Sanborn BM 1996 Epidermal growth factor increases phosphoinositide turnover and intracellular free calcium in an immortalized human myometrial cell line independent of the arachidonic acid metabolic pathway. Am J Obstet Gynecol 174:676–681

    Article  PubMed  CAS  Google Scholar 

  14. Ku CY, Qian A, Wen Y, Anwer K, Sanborn BM 1995 Oxytocin stimulates myometrial guanosine triphosphatase and phospholipase-C activities via coupling to Gαq/11. Endocrinology 136:1509–1515

    Article  PubMed  CAS  Google Scholar 

  15. Arnaudeau A, Lepretre N, Mironneau J 1994 Oxytocin mobilizes calcium from a unique heparin-sensitive and thapsigargin-sensitive store in single myometrial cells from pregnant rats. Pflug Arch 428:51–59

    Article  CAS  Google Scholar 

  16. Phaneuf S, Carrasco MP, Europe-Finner GN, Hamilton CH, Lopez Bernal A 1996 Multiple G proteins and phospholipase C isoforms in human myometrial cells: implication of oxytocin action. J Clin Endocrinol Metab 81:2098–2103

    Article  PubMed  CAS  Google Scholar 

  17. Katz A, Wu D, Simon MI 1992 Subunits beta gamma of heterotrimeric G protein activate beta 2 isoforms of phospholipase C. Nature 360:686–689

    Article  PubMed  CAS  Google Scholar 

  18. Strakova Z, Soloff MS 1997 Coupling of oxytocin receptor to G proteins in rat myometrium during labor: G, receptor interaction. Am J Physiol 272:E870–E876

    PubMed  CAS  Google Scholar 

  19. Mironneau J 1990 Ion channels and excitiation-contraction coupling in myometrium. In: Garfield RE (ed) Uterine Contractility. Serono Symposia USA, Norwell MA, pp. 9–19.

    Google Scholar 

  20. Zhuge R Li S, CHen TH, Hsu WH 1995 Oxytocin induced a biphasic increase in the intracellular Ca2+ concentration of porcine myometrial cells: Participation of a pertussis toxin-insensitive G-protein, inositol 1,4,5-trisphosphate-sensitive Ca2+ pools, and Ca2+ channels. Molec Reprod Devel 41:20–28

    Article  CAS  Google Scholar 

  21. Anwer K, Sanborn BM 1989 Changes in intracellular free calcium in isolated myometrial cells: Role of extracellular and intracellular calcium and possible involvement of guanine nucleotide-sensitive proteins. Endocrinology 124:17–23

    Article  PubMed  CAS  Google Scholar 

  22. Monga M, Ku CY, Dodge K, Sanborn BM 1996 Oxytocin-stimulated responses in a pregnant human immortalized myometrial cell line. Biol Reprod 55:427–432

    Article  PubMed  CAS  Google Scholar 

  23. Rendt JM, Toro L, Stefani E, Erulkar SD 1992 Progesterone increases Ca2+ in myometrial cells from immature and nonpregnant adult rats. Am J Physiol 262:C293–301

    PubMed  CAS  Google Scholar 

  24. Wess J. 1997 G-protein-coupled receptors: molecular mechanisms involved in receptor activation and selectivity of G-protein recognition. FASEB J 11:346–354

    PubMed  CAS  Google Scholar 

  25. Liu J, Conklin BR, Blin N, Yun J, Wess J 1995 Identification of a receptor/G-protein contact site critical for signaling specificity and G-protein activation. Proc Natl Acad Sci USA 92:11642–11646

    Article  PubMed  CAS  Google Scholar 

  26. Cotecchia S, Ostrowski J, Kjelsberg MA, Lefkowitz RJ 1993 Discrete amino acid sequences of the a-adrenergic receptor determine the selectivity of coupling to phosphatidylinositol hydrolysis. J Biol Chem 267:1633–1639

    Google Scholar 

  27. Luttrell LM, Ostrowski J, Cotecchia S, Kendall H, Lefkowitz RJ 1993 Antagonism of catecholamine receptor signaling by expression of cytoplasmic domains of the receptors. J Biol Chem 259:1453–1457

    CAS  Google Scholar 

  28. Hawes BE, Luttrell LM, Exum ST, Lefkowitz RJ 1994 Inhibition of G protein-coupled receptor signaling by expression of cytoplasmic domains of the receptor. J Biol Chem 269:15776–15785

    PubMed  CAS  Google Scholar 

  29. Liu J, Wess J 1996 Different single receptor domains determine the distinct G protein coupling profiles of members of the vasopressin receptor family. J Biol Chem 271:8772–8778

    Article  PubMed  CAS  Google Scholar 

  30. Verrall S, Ishii M, Chen M, Wang L, Tram T, Coughlin SR 1997 The thrombin receptor second cytoplasmic loop confers coupling to Gq-like G proteins in chimeric receptors. J Biol Chem 272:6898–6902

    Article  PubMed  CAS  Google Scholar 

  31. Qian A, Wang W, Sanborn BM 1997 Evidence for the involvement of several intracellular domains in the coupling of oxytocin receptor to Gαq/11. Cellular Signalling, in press

    Google Scholar 

  32. Conklin BR, Herzmark P, Ishida S, Voyno-Yasenetskaya TA, Sun, Farfel Z, Bourne HR 1996 Carboxyl-terminal mutations of Gq alpha and Gs alpha that inhibit the fidelity of receptor activation. Molec Phamacol 50:885–890.

    CAS  Google Scholar 

  33. Wen Y, Anwer K, Singh SP, Sanborn BM 1991 Protein kinase-A inhibits phospholipase-C activity and alters protein phosphorylation in rat myometrial membranes. Endocrinology 131:1377–1382.

    Article  Google Scholar 

  34. Liu M, Simon MI 1996 Regulation by cAMP-dependent protein kinase of a G-protein mediated phospholipase C. Nature 382:83–87.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 1998 Springer Science+Business Media New York

About this chapter

Cite this chapter

Sanborn, B.M., Dodge, K., Monga, M., Qian, A., Wang, W., Yue, C. (1998). Molecular Mechanisms Regulating the Effects of Oxytocin on Myometrial Intracellular Calcium. In: Zingg, H.H., Bourque, C.W., Bichet, D.G. (eds) Vasopressin and Oxytocin. Advances in Experimental Medicine and Biology, vol 449. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4871-3_35

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-4871-3_35

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-7210-3

  • Online ISBN: 978-1-4615-4871-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics