BK Channels Regulate Myometrial Contraction by Modulating Nuclear Translocation of NF-κB

The large-conductance Ca2+-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-kappa B (NF-kappa B) activation in macrophages. In the uterus, NF-kappa B 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-kappa B translocation into the nucleus. We compared the effects of BK channel modulation to those of LPS on NF-kappa B 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-kappa B 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 Ca2+-activated K+ channel protein 3 had an effect on NF-kappa B translocation. Additionally, collagen-based assays showed that paxilline induced contraction ofhTERTcellsanduterine myocytes. This was dependent upon cyclooxygenase-2 activity. Moreover, paxilline-induced contractility and increased cyclooxygenase-2 expression both depended on availability of free NF-kappa B. This study suggests that BK channels regulate myometrial contraction, in part, by modulating nuclear translocation of NF-kappa B.