Melatonin synergizes with oxytocin to enhance contractility of human myometrial smooth muscle cells.
BACKGROUND
Studies have shown that labor occurs primarily in the night/morning hours. Recently, we identified the human myometrium as a target for melatonin (MEL), the neuroendocrine output signal coding for circadian night.


OBJECTIVE
The purpose of this study was to determine the effects of MEL on contractility and the contractile machinery in telomerase-immortalized human myometrial cells.


METHODS
To ascertain the effect of MEL on myometrial contractility in vitro, we performed gel retraction assays with cells exposed to iodomelatonin +/- oxytocin (OT). The effects of iodomelatonin on gap junctions were also investigated. Additionally, expression levels of the type 2 MEL receptor (MT2R) were assessed in myometrial biopsies from term pregnant women with or without labor.


RESULTS
MEL was found to synergistically enhance OT-induced contractility via the MT2R, which is coupled to a protein kinase C-dependent increase in phosphorylation of the myosin light chain protein. MT2R expression was markedly elevated in samples from pregnant women who had entered labor, as compared to matched nonlaboring pregnant women. MEL increased expression of the gap junction protein, connexin 43. In vitro dye spread assays showed that MEL-treated cells displayed substantially increased intercellular coupling. Increases in connexin 43 mRNA and cell to cell coupling were also found to be mediated via the MT2R in a protein kinase C-dependent manner.


CONCLUSIONS
MEL synergizes with OT to promote myometrial cell contractions and to facilitate gap junction activity in vitro. Such a synergy in vivo would promote coordinated and forceful contractions of the late term pregnant uterus necessary for parturition.
Sharkey
James T
JT
Florida State University College of Medicine, Tallahassee, Florida 32306-4300, USA.
Puttaramu
Roopashri
R
Word
R Ann
RA
Olcese
James
J
D002478:Cells, Cultured; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007743:Labor, Obstetric / Q000378:metabolism / Q000502:physiology; D008550:Melatonin / Q000378:metabolism / Q000494:pharmacology*; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D009215:Myometrium / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010121:Oxytocin / Q000378:metabolism / Q000494:pharmacology*; D036801:Parturition / Q000378:metabolism / Q000502:physiology; D011247:Pregnancy; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000378:metabolism; D018045:Receptors, Oxytocin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014590:Uterine Contraction / Q000187:drug effects / Q000378:metabolism
D018031:Connexin 43; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D018045:Receptors, Oxytocin; D010121:Oxytocin; D008550:Melatonin