title: BK channels regulate myometrial contraction by modulating nuclear translocation of NF-κB.
abstract: The large-conductance Ca(2+)-activated K(+) (BK) channel plays an essential role in maintaining uterine quiescence during pregnancy. Growing evidence has shown a link between the BK channel and bacterial lipopolysaccharide (LPS)-induced nuclear factor-κB (NF-κB) activation in macrophages. In the uterus, NF-κB activation plays an important role in inflammatory processes that lead to parturition. Our objective was to determine whether the BK channel regulates uterine contraction, in part, by modulating NF-κB translocation into the nucleus. We compared the effects of BK channel modulation to those of LPS on NF-κB nuclear translocation and contraction in an immortalized human myometrial cell line (human telomerase reverse transcriptase [hTERT]) and uterine myocytes. Our results showed that BK channel inhibitors paxilline and penitrem A induced translocation of NF-κB into the nucleus in both hTERT cells and uterine myocytes to a similar extent as LPS treatment, and LPS and paxilline similarly reduced BK channel currents. Conversely, neither BK channel openers nor blockade of the small conductance Ca(2+)-activated K(+) channel protein 3 had an effect on NF-κB translocation. Additionally, collagen-based assays showed that paxilline induced contraction of hTERT cells and uterine myocytes. This was dependent upon cyclooxygenase-2 activity. Moreover, paxilline-induced contractility and increased cyclooxygenase-2 expression both depended on availability of free NF-κB. This study suggests that BK channels regulate myometrial contraction, in part, by modulating nuclear translocation of NF-κB.
authors.affiliation: Center for Women's Reproductive Sciences Research, Department of Obstetrics and Gynecology, Basic Science Division, Washington University in St Louis, St Louis, Missouri 63110.
authors.forename: Youe
authors.initials: Y
authors.lastname: Li
authors.forename: Ramón A
authors.initials: RA
authors.lastname: Lorca
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Ma
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rhodes
authors.forename: Sarah K
authors.initials: SK
authors.lastname: England
mesh_terms: D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D007211:Indoles; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D008070:Lipopolysaccharides; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009215:Myometrium / Q000502:physiology*; D011247:Pregnancy; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D014590:Uterine Contraction
chemical_list: D007211:Indoles; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; C048220:paxilline; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human