Center for Women's Reproductive Sciences Research, Department of Obstetrics and Gynecology, Basic Science Division, Washington University in St Louis, St Louis, Missouri 63110.
Endocrinology. 2014 Aug;155(8):3112-22. doi: 10.1210/en.2014-1152. Epub 2014 Jun 10.
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.
大电导钙激活钾（BK）通道在维持妊娠期间子宫静止中起着至关重要的作用。越来越多的证据表明，BK 通道与巨噬细胞中细菌脂多糖（LPS）诱导的核因子-κB（NF-κB）激活之间存在联系。在子宫中，NF-κB 的激活在导致分娩的炎症过程中起着重要作用。我们的目的是确定 BK 通道是否通过调节 NF-κB 向核内易位来部分调节子宫收缩。我们比较了 BK 通道调节与 LPS 对 NF-κB 核易位和在永生化人子宫平滑肌细胞系（人端粒酶逆转录酶 [hTERT]）和子宫平滑肌细胞中的收缩的影响。我们的结果表明，BK 通道抑制剂巴卡丁和戊曲胺 A 诱导 NF-κB 向核内易位的程度与 LPS 处理相似，并且 LPS 和巴卡丁同样减少了 BK 通道电流。相反，BK 通道开放剂或小电导钙激活钾通道蛋白 3 的阻断均对 NF-κB 易位没有影响。此外，基于胶原的测定表明，巴卡丁诱导 hTERT 细胞和子宫平滑肌细胞收缩。这依赖于环氧化酶-2 活性。此外，巴卡丁诱导的收缩性和增加的环氧化酶-2 表达均取决于游离 NF-κB 的可用性。这项研究表明，BK 通道通过调节 NF-κB 的核易位来调节子宫平滑肌收缩。
