Phorbol ester treatment of human myometrial cells suppresses expression of oxytocin receptor through a mechanism that does not involve activator protein-1

Jun 8, 2006American journal of physiology. Endocrinology and metabolism

Phorbol ester reduces oxytocin receptor levels in human uterine muscle cells without using activator protein-1

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Abstract

Activation of PKC using phorbol ester significantly decreased oxytocin receptor (OTR) expression within 6 hours.

Stimulation of PKC resulted in a significant increase in the levels of AP-1 subunits c-Jun and c-Fos.
A significant decrease in OTR mRNA was observed within 6 hours of PKC activation.
OT binding decreased significantly by 24 hours following PKC stimulation.
Overexpression of c-Jun and c-Fos did not affect OTR expression in the cell cultures.
No changes in c-Fos or c-Jun levels were detected in human intrauterine tissues at labor onset.

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Oxytocin (OT) is a potent uterine agonist. Its receptor (OTR) is a G protein-coupled receptor that is downregulated by prolonged exposure to OT. We hypothesized that activation of PKC mediated this OT-induced decrease in OTR expression. Diminished PKC activity in late pregnancy could underlie the increased expression of uterine OTR preceding labor onset. Using cell cultures of transformed human uterine myocytes, we determined the effects of PKC agonists and antagonists on the expression of OTR. We also explored the effects of overexpression of activator protein-1 (AP-1, a mediator of many PKC- and phorbol ester-induced effects) using adenoviral expression vectors for the AP-1 subunits c-Jun and c-Fos. Stimulation of PKC using the phorbol ester 12-O-tetradecanoylphorbol 13-acetate caused a rapid, significant (P < or = 0.05) increase in c-Jun and c-Fos concentrations but a significant decrease in mRNA for OTR within 6 h followed by a significant decrease in OT binding by 24 h. Adenoviral infection of the cells with expression vectors for c-Jun and c-Fos increased the AP-1 subunits but had no effect on OTR expression. Furthermore, there were no changes in c-Fos or c-Jun levels in human intrauterine tissues around the time of labor onset, as measured by Western analyses. We conclude that phorbol ester treatment decreases OTR expression, likely through a mechanism that does not involve AP-1.

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Phorbol ester treatment of human myometrial cells suppresses expression of oxytocin receptor through a mechanism that does not involve activator protein-1

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