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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1128
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 10 4015-4019
Copyright © 2007 by The Endocrine Society

Transcriptional Inhibition of Oxytocin Receptor Expression in Human Myometrial Cells by Melatonin Involves Protein Kinase C Signaling

James Sharkey and James Olcese

Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida 32306-4300

Address all correspondence and requests for reprints to: James Olcese, Ph.D., Department of Biomedical Sciences, Florida State University College of Medicine, 1115 West Call Street, Tallahassee, Florida 32306-4300. E-mail: james.olcese{at}med.fsu.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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 understand better 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 human telomerase reverse transcriptase 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 melatonin 2 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 the protein kinase C inhibitor C1.

Conclusions: Melatonin, like oxytocin, can negatively regulate oxytocin receptor transcription in human myometrial cells via modulation of protein kinase C 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.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
LATE IN PREGNANCY the human myometrium up-regulates expression of the oxytocin receptor (OTR), a G protein-coupled receptor that transduces the oxytocin (OT) signal primarily via the G{alpha}q/11 subunit to activate phospholipase C (PLC) and thereby increase intracellular calcium levels and inositol trisphosphate production (1). A number of protein kinase cascades are also induced by OT, including protein kinase C (PKC) and the p42/44 MAPK (2). At parturition the ligand bound OTR contributes to the dramatic increase in uterine contractions. Conversely, the OTR antagonist atosiban is used to delay preterm labor in humans (3).

Melatonin (MEL) was reported by Martensson et al. (4) to significantly potentiate the contractility of pregnant human myometrial tissues in vitro after application of norepinephrine. This was considered to involve the well-described inhibition of cAMP production by MEL via its Gi-mediated suppression of adenylyl cyclase activity and/or the PLC-mediated calcium-elevating effects of MEL (5).

In a previous study (6), we determined that the mRNA and protein expression levels of the MEL receptors (MTR; especially the MT2R) were substantially repressed during late pregnancy in the absence of labor. Apart from the hypothesized procontractile activity of MEL, its role in the human myometrium remains unclear. To facilitate a better understanding of MEL’s functions in this tissue, we investigated the influence of MEL on the expression of the OTR in telomerase-immortalized human telomerase reverse transcriptase (hTERT) myometrial cells. This model has been demonstrated to reflect accurately the mature myometrial smooth muscle cell (7, 8), and being a nontumor-derived clonal cell line, it obviates the high variability of responses seen with primary cells, and it is amenable to transfection. Our results reveal a significant regulatory impact of MEL on the transcriptional activity of the OTR gene.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cell culture experiments

hTERT cells were maintained in Ham’s F-12/DMEM with 4.5 g/liter glucose, 3 mM glutamine, penicillin/streptomycin, and 10% Fetal Plus II serum (Valley Biomedical, Winchester, VA). For the intracellular signaling studies, cells were plated into 6-well culture dishes at a density of 20,000 cells/well. Before treatment cells were washed once in complete medium and then exposed in triplicate to either vehicle or chemical agents. Except for the time-course and dose-response studies, cells were typically treated for 4 h with 1 nM MEL. In the case of the pharmacological inhibitors pertussis toxin (LIST, Campbell, CA), U73122 (Tocris, Ellisville, MO), and C1 (Tocris), cells were preincubated for 1 h before MEL exposure. For the determination of OTR transcript turnover rates, the cells were exposed to 5 µM actinomycin (Sigma, St. Louis, MO) with or without 1 nM iodomelatonin (I-MEL; Tocris). The cells were then harvested at 0, 2, 4, 6, 12, and 24 h after treatment.

Quantitative PCR

Cellular total RNA was extracted with the RNEasy kit (QIAGEN, Valencia, CA) according to the manufacturer’s protocol. The RNA concentration was measured with the Nanodrop photometer and then reverse transcribed to cDNA by means of the iScript reverse transcription system (Bio-Rad Laboratories, Foster City, CA). Quantitative real-time PCR was performed on a Bio-Rad iCycler using iQ SYBR Green Supermix (Bio-Rad), together with 1 µl of sense and antisense primers (10 pmol/µl) of the transcript of interest and 2 µl of template cDNA. The following thermal cycling parameters were used: initial heat activation of the DNA-polymerase was performed at 95 C for 5 min. Thereafter 40 cycles at 95 C (15 sec), 58 C (30 sec), and 72 C (30 sec) were run. After thermocycling the iCycler performs an automatic melting curve, which entails cooling to 55 C for 10 sec and then increasing temperatures in 0.2 C increments up to 90 C. This controls for primer-dimer formation and other nonspecific effects. Quantification of the data were achieved by the Bio-Rad iCycler software using a standard curve from a primer-specific dilution series for the PCR product. Data were normalized against expression of the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The primer sequences used for OTR, MT1R, MT2R, and GAPDH quantification are as follows:

OTR forward, 5'-TGG CGG AGC ACA GG-3', OTR reverse, 5'-GTG TCA GCA GTC AAG C-3'; MT1R forward, 5'-TCC TGG TCA TCC TGT CCG TGT ATC-3', MT1R reverse, 5'-CTG CTG TAC AGT TTG TCG TAC TTG-3'; MT2R forward, 5'-TCC TGG TGA TCC TCT CCG TGC TCA-3'; MT2R reverse, 5'-AGC CAG ATG AGG CAG ATG TGC AGA-3'; and GAPDH forward, 5'-GTC TTC ACC ACC ATG GAG-3', GAPDH reverse, 5'-GTC ATG GAT AAC CTT GGC-3'.

Statistical analyses

Experiments were repeated at least three times. Replicate values for each data point were averaged and differences statistically analyzed using a one-way ANOVA followed by the Bonferroni post hoc test (Prism; GraphPad, San Diego, CA) with P < 0.05 as the criterion level for significance. For the determination of OTR mRNA turnover, the data were analyzed using a nonlinear regression (GraphPad Prism).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
MEL, much like the OTR ligand oxytocin, was found to substantially reduce OTR expression in immortalized myometrial smooth muscle cells. Concentrations at or above a physiological concentration of 1 nM were equally effective, implying saturation of available receptors (Fig. 1AGo). This is feasible, given that the affinity constants for both MT1R and MT2R are less than 300 pM. Time-course studies showed that the inhibitory effects of MEL at 2 and 4 h were significant (P < 0.05), whereas a maximal effect (significantly lower than the 2 h effect) was seen by 12 h of treatment (Fig. 1BGo). No effects of MEL on the expression of MTRs were noted under these conditions (Fig. 2Go). Similarly, the expression of OTR mRNA did not change with time in the absence of agonist (data not shown).


Figure 1
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  		FIG. 1. I-MEL inhibits OTR mRNA levels in hTERT cells after 4-h exposure to various doses (A) and after exposure of cells to 1 nM for 2, 4, or 12 h (B). *, Statistical difference relative to controls (P < 0.05); **, statistically lower than values at 2 h.

 

Figure 2
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  		FIG. 2. A, The inhibition of OTR mRNA expression by I-MEL (1 nM, 4 h) was significantly attenuated by the MT2R antagonist 4P-PDOT (10 nM). The antagonist alone was without effect. B, MEL (1 nM, 4 h) had no effect on the expression levels of MT1R or MT2R. *, Statistical difference relative to control (P < 0.05).

 
The inhibitory action of MEL (1 nM for 4 h) on OTR expression is receptor mediated inasmuch as the specific MTR antagonist 4-phenyl-2-proprionamidotetralin (4P-PDOT) can largely block this effect (Fig. 2AGo). The antagonist alone had no effect on OTR mRNA levels. At the dose of 4P-PDOT that was used (10 nM), only MT2Rs are likely to be blocked (5); thus, we concluded that primarily the MT2R mediates the inhibitory action of MEL on OTR mRNA expression in these cells. Both MT1R and MT2R were identified in hTERT cells by quantitative PCR analysis, and neither changed its expression level after short-term MEL exposure (Fig. 2BGo).

The inhibitory effect of MEL largely mimics the effect of oxytocin on OTR expression; hence, there may be commonality in their signaling pathways. MTRs are coupled to inhibitory G protein-coupled mechanisms; hence, we examined whether this pathway is necessary for the inhibitory action of MEL on OTR mRNA expression. Cells were preincubated with pertussis toxin (100 ng/ml), which ADP ribosylates the G{alpha}i subunit, thereby preventing it from signaling. This treatment had no effect on the ability of MEL (1 nM for 4 h) to suppress OTR mRNA expression (Fig. 3Go).


Figure 3
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  		FIG. 3. Pertussis toxin (PTX; 100 ng) does not prevent the inhibitory action of I-MEL (1 nM for 4 h) on OTR mRNA expression in human myometrial smooth muscle cells. *, Statistical difference relative to control (P < 0.05).

 
To establish whether the decline in OTR mRNA levels after application of MEL is due to inhibitory transcriptional mechanisms as opposed to a shortening of half-life of the OTR transcript, we exposed cells to the transcriptional blocker actinomycin D (5 µg/ml). As would be expected, the levels of the OTR transcript decay exponentially after this treatment alone with a half-life of 1.48 h. The presence of 1 nM I-MEL had no additional effect on the rate of OTR mRNA degradation (Fig. 4Go), indicating that MEL’s actions are likely to involve transcriptional repression.


Figure 4
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  		FIG. 4. The rate of decline of the myometrial OTR transcript after exposure to I-MEL (1 nM) for 2, 4, 6, 12, or 24 h is identical with that after no I-MEL when transcription is blocked by preincubation of cells with actinomycin D (5 µg/ml). No additional effect was noted when actinomycin and I-MEL (1 nM) were given together.

 
Both MTR and OTR use the PLC signaling pathway upon activation by their cognate ligands. We therefore assessed the effect of PLC blockade on MEL’s action to suppress OTR transcription. The PLC inhibitor U73122 at a dose of 1 µM prevented MEL’s inhibitory effect (Fig. 5Go) as well as preventing OT’s inhibitory effect (data not shown). The inhibition of OTR transcription could be reinstated by addition of phorbol 12,13-dibutyrate (10 nM), a phorbol ester that directly activates PKC.


Figure 5
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  		FIG. 5. Pharmacological inhibition of PLC activity with U73122 (1 µM) prevents I-MEL inhibition (1 nM for 4 h) of OTR transcription in cultured human myometrial cells. The PKC activator phorbol,12,13-dibutyrate (PDBu; 10 nM) also inhibits OTR transcription and can circumvent the effect of U73122. *, Statistical difference relative to control (P < 0.05).

 
To confirm that PKC signaling is required for MEL’s inhibitory effect on OTR transcription, cells were pretreated in the presence or absence of 10 µM of the PKC inhibitor C1 for 1 h. Inhibition of PKC prevented I-MEL (1 nM for 4 h) from lowering OTR transcription in immortalized myometrial smooth muscle cells (Fig. 6Go).


Figure 6
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  		FIG. 6. The inhibitory effect of 1 nM I-MEL (4 h) on OTR transcription in hTERT cells is prevented by preincubation with the PKC inhibitor C1 (10 µM). *, Statistical difference relative to control (P < 0.05).

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
An influence of MEL on parturition in rodents was suggested recently (9) by findings that female rats lacking endogenous MEL synthesis failed to deliver their young exclusively during the daytime, which is the normal birthing phase for these nocturnal animals. Instead, they gave birth randomly across the 24-h light-dark cycle. MEL was effective in restoring the daytime birth pattern when it was administered in the evening (the time at which endogenous MEL secretion would normally rise) but was ineffectual when given in the morning or continuously. These interesting results demonstrate that the timing of birth in the rat is under circadian control and that MEL may serve as a key circadian signal for this event.

The precise mode of action of MEL in the uterine myometrium is still unclear. Earlier reports (10, 11) described direct inhibitory effects of pharmacological doses of MEL on uterine contractility in rodents as well as the presence of MEL-specific binding sites in the uterus (12). Later studies confirmed inhibitory effects of MEL on uterine contractility in vitro after stimulation by oxytocin (13, 14). The large-conductance, calcium-dependent potassium channel (BKCa) has also been identified as a target for MEL action in rat myometrial cells (15). In this study, MEL modulated the BKCa channel via the Gi-mediated inhibition of cAMP signaling (thereby inhibiting mechanisms that promote myometrial quiescence) in nonpregnant but not pregnant myometrium. In contrast, MEL consistently activated the Gq/PLC pathway in myometrial cells, which promotes contractility. The BKCa potassium channel is the predominant potassium channel in the nonpregnant and pregnant myometrium of the human (16) and has been implicated in maintaining uterine quiescence during pregnancy (17).

Given that human labor and delivery are, in contrast to the nocturnal rodent, statistically more common during the nocturnal phase (18, 19, 20), it would seem reasonable to propose that MEL may contribute to human parturition. Previously we demonstrated MTR mRNA and protein expression in the human myometrium during pregnancy without labor and in nonpregnant women (6). A substantial decline in MTR expression (compared with nonpregnant tissues) was seen in the myometria of women in late pregnancy before the onset of labor. Additionally, the inhibitory effects of MEL on intracellular cAMP signaling that were typical to cultured myometrial cells of nonpregnant women were absent in the cells of pregnant women, possibly because of the low MTR expression in the latter case. Our finding of low myometrial MTR expression in late pregnancy may represent a physiological mechanism to balance contractile against quiescent mechanisms until the proper phase of late gestation has been reached. Changes in myometrial receptor expression and cAMP signaling mechanisms during pregnancy are well known. For example, the expression of the stimulatory G protein Gs{alpha} is up-regulated and then subsequently down-regulated before the onset of labor (21). Conversely, the myometrial expression of the prostaglandin F2{alpha} receptor is dramatically down-regulated in pregnancy when compared with nonpregnant tissue, but it then increases dramatically with labor (22).

Substantial evidence points to a role for the pituitary hormone OT in stimulating myometrial contractility. Many but not all studies have found that the expression of the OTR in the human myometrium is significantly up-regulated in late pregnancy (cf. Ref. 3 for review), when nocturnal plasma OT levels are also increasing (23). Continuous infusion of OT agonists is commonly used to induce labor. However, prolonged labor induction by application of continuous OT is effective only when high amounts of the hormone are given due to OTR down-regulation at both the transcriptional and posttranslational levels (24). Despite numerous studies demonstrating significant modulation by steroids, cytokines, etc., there remains a paucity of data on the specific regulatory mechanisms controlling the OTR gene in the human myometrium (cf. Ref. 25).

The results of our present studies provide novel insights into the regulation of OTR expression in human myometrial smooth muscle cells. The effects of MEL on OTR mRNA levels are remarkably similar to those of the OTR ligand itself inasmuch as OT suppression of OTR in myometrial cells also involves PKC signaling (2, 25). At 1 nM, a dose approximating nocturnal levels in late pregnancy (26), and at exposure times of longer than 2 h, MEL suppressed OTR expression by 30–60% (Fig. 1Go). No significant additive effects of OT + MEL were noted (data not shown), suggesting near maximal recruitment of PLC/PKC pathways by MEL. This notion is further supported by the nonadditive effects of MEL and the PKC activator phorbol,12,13-dibutyrate PDBu on OTR mRNA levels (Fig. 5Go).

In our in vitro experiments, neither MEL nor OT was tested for possible effects on the contractile activity of human myometrial cells. Thus, it is not possible at this time to draw any definitive conclusions regarding the influence of MEL on contractility of the pregnant human uterus. Earlier studies in pregnant nonhuman primates (27) reported no alteration of rhythmic uterine contractility after blockade of MEL secretion by constant light exposure or after subsequent MEL infusion. Whether this reflects species-specific differences in myometrial MTR expression or underscores endocrine redundancy in the mechanisms controlling uterine contractility remains to be investigated.

The MEL-dependent inhibition of OTR transcription that we have identified in human myometrial cells can be blocked by the antagonist 4P-PDOT (Fig. 2Go) at a dose that is selective for the MT2R (5). The inhibition of OTR transcription by MEL can also be relieved by pharmacological blockade of PLC (Fig. 5Go) and PKC (Fig. 6Go), pointing to the involvement of a PLC/PKC signaling pathway in this effect. MTRs have been shown to couple to PKC in other cell systems (5, 28). Although kinase cascades are known to modulate numerous transcription factors, the precise molecular mechanism for PKC-mediated suppression of myometrial OTR transcription, by either OT or MEL, remains to be elucidated.

The findings in the present report illuminate new avenues for a better understanding of human myometrial physiology. The interplay between a circadian signal, such as MEL, and a contractile stimulus, such as OT, during the course of late pregnancy may contribute to the maintenance of normal term pregnancy as well as the circadian timing of labor. Further characterization of such regulatory networks in the human uterus can be expected to be of value in the search for novel therapies to prevent preterm labor, the etiology of which is still not clear.


   Footnotes
 
The authors are grateful to Dr. A. Word, M.D., for providing the hTERT cell line. We also thank Dr. D. Resuehr, Dr. R. Puttaramu, and K. Dietz for helpful advice and assistance. This contribution represents a portion of the doctoral studies of J.S.

Disclosure Summary: The authors have nothing to declare.

First Published Online August 28, 2007

Abbreviations: BKCa, Large-conductance, calcium-dependent potassium channel; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; hTERT, human telomerase reverse transcriptase; I-MEL, iodomelatonin; MEL, melatonin; MTR, MEL receptor; OT, oxytocin; OTR, OT receptor; PKC, protein kinase C; PLC, phospholipase C.

Received May 22, 2007.

Accepted July 19, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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J. T. Sharkey, R. Puttaramu, R. A. Word, and J. Olcese
Melatonin Synergizes with Oxytocin to Enhance Contractility of Human Myometrial Smooth Muscle Cells
J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 421 - 427.
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