The oxytocin receptor

doi:10.1016/S1043-2760(03)00080-8

Trends in Endocrinology & Metabolism

Volume 14, Issue 5, July 2003, Pages 222-227

https://doi.org/10.1016/S1043-2760(03)00080-8 Get rights and content

Abstract

Novel sites of oxytocin receptor expression have recently been detected, including breast cancer cells, bone cells, myoblasts, cardiomyocytes and endothelial cells. These discoveries have greatly expanded the possible spectrum of oxytocin action beyond its classic role as an inducer of uterine contractions and milk ejection. Additional advances in the understanding of oxytocin receptor structure–function relationships, receptor trafficking and novel receptor-linked signaling cascades have made this receptor an attractive model for the study of G-protein-linked receptor function. Finally, the tocolytic efficiency of the oxytocin receptor antagonist atosiban, recently approved for clinical use in Europe, has opened new avenues for the prevention and treatment of preterm labor.

Section snippets

Regulation of OXTR expression

Unlike many other members of the GPCR superfamily, OXTR expression undergoes dramatic and cell-specific up- and downregulation. In the uterus, the expression of OXTR is upregulated by up to two orders of magnitude during gestation, and this leads to a strong increase in uterine sensitivity towards OT [9]. After parturition, uterine OT-binding sites undergo a rapid decrease, whereas mammary gland OT receptor expression remains raised throughout the period of lactation 9, 10. This tissue-specific

Structural features involved in ligand binding

The combined evidence from studies involving site-directed mutagenesis, photoaffinity labeling and molecular modeling indicate that the cyclic part of the OT molecule is lodged in the upper one-third of the receptor binding pocket and interacts with transmembrane domains 3, 4 and 6, whereas the linear C-terminal part of the OT molecule remains closer to the surface and interacts with transmembrane domains 2 and 3, in addition to the first extracellular loop [28] (Fig. 1).

Photoaffinity labeling

Signaling mechanisms

Activation of OT receptors located on smooth muscle cells, such as uterine myometrial cells or mammary gland myoepithelial cells, induces contraction, which is triggered by an increase in intracellular Ca²⁺ that leads to a calmodulin-mediated activation of myosin light-chain kinase [34]. The increase in intracellular Ca²⁺ involves a Gα_q/11-mediated stimulation of PLC activity [8]. An OT-induced, nifedipine-insensitive entry of extracellular Ca²⁺ through capacitative Ca²⁺ entry has also been

Structural features involved in signaling

The regions of the OT receptor implicated in G-protein interactions have been delineated by examining the inhibitory effects of coexpression of different intracellular domains of the receptor, and by exchanging domains between the OT receptor and the V₂ and V_1a vasopressin receptors. The results of these studies indicate that all four intracellular domains are involved in coupling to G_q/11 34, 48. Molecular modeling studies suggested that the activation process induced by agonist binding

Receptor internalization and cellular localization

Another common feature of GPCRs is their rapid internalization and disappearance from the cell surface after their activation. This phenomenon has been observed for the OT receptor by confocal microscopy, with the use of different approaches to epitope tag the receptor (Fig. 3a) 52, 53, 54. After agonist addition, β-arrestin–green fluorescent protein (GFP) is recruited from the cytosol to the plasma membrane, where it binds to the OT receptor. The fusion of GFP to β-arrestin has enabled the

OT receptors mediating ‘non-classic’ effects of OT

Prompted by the discovery of OT receptor expression at several peripheral sites, the spectrum of proposed biological functions of OT has recently expanded. Actions on pituitary, kidney, thymus and the male reproductive system have recently been reviewed elsewhere 6, 7. The following paragraphs focus on some recent developments.

Acknowledgements

We thank Anne Brusby for discussion and critical reading of the article and C. Balthazar for secretarial assistance. Work in the authors' laboratory has been supported by grants from the Canadian Institutes for Health Research (CIHR) and from Wyeth-Ayerst Canada Inc. S.A.L. is a holder of a Canada Research Chair.

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