Chapter

Vasopressin and Oxytocin

Volume 449 of the series Advances in Experimental Medicine and Biology pp 287-295

Genomic and Non-Genomic Mechanisms of Oxytocin Receptor Regulation

  • H. H. ZinggAffiliated withLaboratory of Molecular Endocrinology, Royal Victoria Hospital, McGill University
  • , E. GrazziniAffiliated withLaboratory of Molecular Endocrinology, Royal Victoria Hospital, McGill University
  • , C. BretonAffiliated withLaboratory of Molecular Endocrinology, Royal Victoria Hospital, McGill University
  • , A. LarcherAffiliated withLaboratory of Molecular Endocrinology, Royal Victoria Hospital, McGill University
  • , F. RozenAffiliated withLaboratory of Molecular Endocrinology, Royal Victoria Hospital, McGill University
  • , C. RussoAffiliated withLaboratory of Molecular Endocrinology, Royal Victoria Hospital, McGill University
  • , G. GuillonAffiliated withINSERM, Unité 469
  • , B. MouillacAffiliated withINSERM, Unité 469

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Abstract

Our recent studies have shown that regulation of uterine oxytocin (OT) binding involves at least two different mechanisms: Estradiol (E2)-induced upregulation is accompanied by an increase in OT receptor (OTR) mRNA accumulation, implying that the E2 effect is mediated via increased OTR gene transcription and/or OTR mRNA stabilization. In contrast, P (P)-induced OTR down-regulation occurs via a novel non-genomic mechanism, involving a direct interaction of P with the OTR at the level of the cell membrane. We found that P specifically binds to the OTR and inhibits its ligand binding and signalling functions. Physiological levels of P repress in vitro the ligand binding capacity (Bmax) of the OTR by >50%. When expressed in CHO cells, the OTR provides a high affinity (Kd: 20nM) membrane binding site for P. OT-induced inositol phosphate production and intracellular calcium mobilization is inhibited 85% and 90%, respectively, by P. These effects are specific as signalling and binding functions of the closely related Vla vasopressin receptor remain unaffected by P, and as other, related steroids are devoid of any effect on OTR binding or signalling functions. The present observation of a specific interaction of a steroid with a G-protein-linked receptor defines a new mechanism of non-genomic steroid action and uncovers a novel level of crosstalk between steroid and peptide hormone action.