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Inhibition of oxytocin receptor function by direct binding of progesterone

Abstract

The steroid hormone progesterone (P4) is essential for establishing and maintaining pregnancy in mammals1,2,3. One of its functions includes maintenance of uterine quiescence by decreasing uterine sensitivity to the uterotonic peptide hormone oxytocin3,4,5. Although it is generally held that steroid hormones such as P4 act at a genomic level by binding to nuclear receptors and modulating the expression of specific target genes6, we show here that the effect of P4 on uterine sensitivity to oxytocin involves direct, non-genomic action of P4 on the uterine oxytocin receptor (OTR), a member of the G-protein-coupled receptor family. P4 inhibits oxytocin binding to OTR-containing membranes in vitro, binds with high affinity to recombinant rat OTR expressed in CHO cells, and suppresses oxytocin-induced inositol phosphate production and calcium mobilization. These effects are highly steroid- and receptor-specific, because binding and signalling functions of the closely related human OTR are not affected by P4 itself but by the P4 metabolite 5β-dihydroprogesterone. Our findings provide the first evidence for a direct interaction between a steroid hormone and a G-protein-coupled receptor and define a new level of crosstalk between the peptide- and steroid-hormone signalling pathways.

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Figure 1: Inhibition of OTR binding capacity by P4.
Figure 2: Specific binding of P4 to the OTR and effect of GTPγS.
Figure 3: Effect of P4 on ligand-induced IP production.
Figure 4: Effect of P4 on OT-stimulated calcium mobilization in OTR-expressing Fura-2-loaded CHO cells.

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References

  1. Csapo, A. I., Puri, C. P. & Tarro, S. Relationship between timing of ovariectomy and maintenance of pregnancy in the guinea-pig. Prostaglandins 22, 131–140 (1981).

    Article  CAS  Google Scholar 

  2. Pepe, G. J. & Albrecht, E. D. Actions of placental and fetal adrenal steroid hormones in primate pregnancy. Endocr. Rev. 16, 608–648 (1995).

    CAS  PubMed  Google Scholar 

  3. Garfield, R. E., Puri, C. P. & Csapo, A. I. Endocrine, structural, and functional changes in the uterus during premature labor. Am. J. Obstet. Gynecol. 142, 21–27 (1982).

    Article  CAS  Google Scholar 

  4. 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 113, 742–749 (1983).

    Article  CAS  Google Scholar 

  5. Soloff, M. S. et al. Regulation of oxytocin receptor concentration in rat uterine explants by estrogen and progesterone. Can. J. Biochem. Cell Biol. 61, 625–630 (1983).

    Article  CAS  Google Scholar 

  6. Tsai, M. J. & O'Malley, B. W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu. Rev. Biochem. 63, 451–486 (1994).

    Article  CAS  Google Scholar 

  7. Larcher, A. et al. Oxytocin receptor gene expression in the rat uterus during pregnancy and the estrous cycle and in response to gonadal steroid treatment. Endocrinology 136, 5350–5356 (1995).

    Article  CAS  Google Scholar 

  8. Elands, J. et al.125I-labelled d(CH2)5[Tyr(Me)2, Thr4, Tyr-NH2(9)]OVT: a selective oxytocin receptor ligand. Eur. J. Pharmacol. 147, 197–207 (1988).

    Article  CAS  Google Scholar 

  9. Pepe, G. J. & Rothchild, I. Acomparative study of serum progesterone levels in pregnancy and in various types of pseudopregnancy in the rat. Endocrinology 95, 275–279 (1974).

    Article  CAS  Google Scholar 

  10. Schmidt, A. et al. Aradioiodinated linear vasopressin antagonist: a ligand with high affinity and specificity for V1a receptors. FEBS Lett. 282, 77–81 (1991).

    Article  CAS  Google Scholar 

  11. Zingg, H. H. in Bailliere's Clinical Endocrinology and Metabolism (eds Sheppard, M. C. & Franklyn, J.A.) 75–96 (Bailliere Tindall, London, (1996)).

    Google Scholar 

  12. Burgisser, E., De Lean, A. & Lefkowitz, R. J. Reciprocal modulation of agonist and antagonist binding to muscarinic cholinergic receptor by guanine nucleotide. Proc. Natl Acad. Sci. USA 79, 1732–1736 (1982).

    Article  ADS  CAS  Google Scholar 

  13. Green, R. D. Reciprocal modulation of agonist and antagonist binding to inhibitory adenosine receptors by 5′-guanylylimidodiphosphate and monovalent cations. J. Neurosci. 4, 2472–2476 (1984).

    Article  CAS  Google Scholar 

  14. Sundaram, H., Newman-Tancredi, A. & Strange, P. G. Characterization of recombinant human serotonin 5HT1A receptors expressed in Chinese hamster ovary cells. Biochem. Pharmacol. 45, 1003–1009 (1993).

    Article  CAS  Google Scholar 

  15. Westphal, R. S. & Sanders-Bush, E. Reciprocal binding properties of 5-hydroxytryptamine type 2C receptor agonists and inverse agonists. Mol. Pharmacol. 46, 937–942 (1994).

    CAS  PubMed  Google Scholar 

  16. Grazzini, E. et al. Membrane-delimited G protein-mediated coupling between V1a vasopressin receptor and dihydropyridine binding sites in rat glomerulosa cells. Mol. Pharmacol. 50, 1273–1283 (1996).

    CAS  PubMed  Google Scholar 

  17. Wassermann, W. J., Pinto, L. H., O'Connor, C. M. & Smith, L. D. Progesterone induces a rapid increase in [Ca2+]inof Xenopus laevis oocytes. Proc. Natl Acad. Sci. USA 77, 1534–1536 (1980).

    Article  ADS  Google Scholar 

  18. Majewska, M. D., Harrison, N. L., Schwartz, R. D., Barker, J. L. & Paul, S. M. Steroid hormone metabolites are barbituarate-like modulators of the GABA receptor. Science 232, 1004–1007 (1986).

    Article  ADS  CAS  Google Scholar 

  19. Wong, M. & Moss, R. L. Patch-clamp analysis of direct steroidal modulation of glutamate receptor-channels. J. Neuroendocrinol. 6, 347–355 (1994).

    Article  CAS  Google Scholar 

  20. Valera, S., Ballivet, M. & Bertrand, D. Progesterone modulates a neuronal nicotinic acetylcholine receptor. Proc. Natl Acad. Sci. USA 89, 9949–9953 (1992).

    Article  ADS  CAS  Google Scholar 

  21. Blackmore, P. F., Fisher, J. F., Spilman, C. H. & Bleasdale, J. E. Unusual steroid specificity of the cell surface progesterone receptor on human sperm. Mol. Pharmacol. 49, 727–739 (1996).

    CAS  PubMed  Google Scholar 

  22. Schumacher, M., Coirini, H., Frankfurt, M. & McEwen, B. S. Localized actions of progesterone in hypothalamus involve oxytocin. Proc. Natl Acad. Sci. USA 86, 6798–6801 (1989).

    Article  ADS  CAS  Google Scholar 

  23. Kimura, T., Tanizawa, O., Mori, K., Brownstein, M. J. & Okayama, H. Structure and expression of a human oxytocin receptor. Nature 356, 526–529 (1992).

    Article  ADS  CAS  Google Scholar 

  24. Chini, B. et al. Tyr115 is the key residue for determining agonist selectivity in the V1a vasopressin receptor. EMBO J. 14, 2176–2182 (1995).

    Article  CAS  Google Scholar 

  25. Grazzini, E. et al. Dual effects of fluoro-aluminate on activation of calcium influx and inhibition of agonist-induced calcium mobilization in rat glomerulosa cells. Cell Calcium 19, 29–41 (1996).

    Article  CAS  Google Scholar 

  26. Guillon, G. et al. Vasopressin stimulates steroid secretion in human adrenal glands: comparison with angiotensin-II effect. Endocrinology 136, 1285–1295 (1995).

    Article  CAS  Google Scholar 

  27. Jeng, Y. J. et al. Molecular cloning and functional characterization of the oxytocin receptor from a rat pancreatic cell line (RINm5F). Neuropeptides 30, 557–65 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Jard, M. Bouvier and A. DeLean for discussion and for comments, N.Gallo-Payet and D. Payet for help with calcium measurements, J. Neculcea for technical help and E.Monaco for secretarial assistance. This research was supported from grants by the MRC of Canada. E.G. is supported by an MRC Fellowship award.

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Correspondence to Hans H. Zingg.

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Grazzini, E., Guillon, G., Mouillac, B. et al. Inhibition of oxytocin receptor function by direct binding of progesterone. Nature 392, 509–512 (1998). https://doi.org/10.1038/33176

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