Context: Our laboratory recently characterized the expression of the melatonin receptors in the human myometrium and showed that the expression of these receptors is suppressed during late pregnancy.

Objective: In an effort to better understand the significance of melatonin in the human myometrium we explored the mechanisms through which this hormone influences the expression of the oxytocin receptor in vitro.

Design: The stable melatonin analog iodomelatonin was presented to cultured telomerase immortalized myometrial cells of the hTERT line under physiological doses and durations. Pharmacological inhibitors of melatonin binding, gene transcription, phospholipase C and protein kinase C signaling were used to define the mechanism of melatonin action.

Results: Our results reveal that melatonin significantly inhibits oxytocin receptor mRNA expression primarily via the MT2 melatonin receptor. The melatonin-dependent decrease in oxytocin receptor transcripts involves suppression of gene transcription rather than enhanced rates of transcript degradation. Melatonin effects were abolished by pretreating the cells with the phospholipase C inhibitor U73122 or with the protein kinase C (PKC) inhibitor C1.

Conclusions: Melatonin, like oxytocin, can negatively regulate oxytocin receptor transcription in human myometrial cells via modulation of PKC signaling. This is consistent with the hypothesis that the reduced melatonin receptor expression during late pregnancy, which occurs at a time when oxytocin receptors are up-regulated, may be physiologically important for the subsequent timing of labor.