Kv7 potassium channels in airway smooth muscle cells: signal transduction intermediates and pharmacological targets for bronchodilator therapy
Kv7 potassium channels in airway smooth muscle cells: signal transduction intermediates and pharmacological targets for bronchodilator therapy
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DOI：
10.1152/ajplung.00194.2011
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发表时间：
2012-01-01
影响因子：
4.9
通讯作者：
Byron, Kenneth L.
中科院分区：
文献类型：
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作者：
Brueggemann, Lioubov I.;Kakad, Priyanka P.;Byron, Kenneth L.
Brueggemann LI，Kakad PP，Love RB，Solway J，Dowell ML，Cribbs LL，Byron KL.气道平滑肌细胞kv 7钾通道：支气管扩张剂治疗的信号转导中间体和药理学靶点。美国生理学杂志肺细胞分子生理学302：L120-L132，2012年。首次发表于2011年9月30日; doi：10.1152/ajplung.00194.2011.-采用定量逆转录聚合酶链反应（qRT-PCR）、膜片钳电生理和精密肺切片研究豚鼠和人气道平滑肌细胞（ASMCs）Kv 7（KCNQ）电压激活钾通道的表达和功能。qRT-PCR显示豚鼠和人ASMCs中多个KCNQ基因表达。在新鲜分离的豚鼠和人ASMCs中测量具有Kv 7电流的电生理学和药理学特征的电流。在豚鼠ASMCs，Kv 7电流显着抑制支气管收缩激动剂乙酰甲胆碱（100 nM）或组胺（30 μ M）的应用，但电流幅度恢复通过添加Kv 7通道激活剂，氟吡汀（10 μ M）。另一种Kv7.2-7.5通道激活剂瑞替加滨以及塞来昔布和2，5-二甲基塞来昔布也显著增强豚鼠ASMCs的Kv 7电流。在精确切割的人肺切片中，在氟吡汀的存在下，组胺引起的气道收缩显著减少。豚鼠和人ASMCs的Kv 7电流均被Kv 7通道阻断剂XE 991抑制。在人肺切片中，XE 991诱导了强烈的气道收缩，通过加入钙通道阻滞剂维拉帕米完全逆转。这些发现表明，ASMCs中的Kv 7通道在气道直径的调节中起着重要作用，并且可能被靶向抑制以减轻由高浓度的支气管收缩剂激动剂诱导的气道过度收缩。
Brueggemann LI, Kakad PP, Love RB, Solway J, Dowell ML, Cribbs LL, Byron KL. Kv7 potassium channels in airway smooth muscle cells: signal transduction intermediates and pharmacological targets for bronchodilator therapy. Am J Physiol Lung Cell Mol Physiol 302: L120-L132, 2012. First published September 30, 2011; doi: 10.1152/ajplung.00194.2011.-Expression and function of Kv7 (KCNQ) voltage-activated potassium channels in guinea pig and human airway smooth muscle cells (ASMCs) were investigated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), patch-clamp electrophysiology, and precision-cut lung slices. qRT-PCR revealed expression of multiple KCNQ genes in both guinea pig and human ASMCs. Currents with electrophysiological and pharmacological characteristics of Kv7 currents were measured in freshly isolated guinea pig and human ASMCs. In guinea pig ASMCs, Kv7 currents were significantly suppressed by application of the bronchoconstrictor agonists methacholine (100 nM) or histamine (30 mu M), but current amplitudes were restored by addition of a Kv7 channel activator, flupirtine (10 mu M). Kv7 currents in guinea pig ASMCs were also significantly enhanced by another Kv7.2-7.5 channel activator, retigabine, and by celecoxib and 2,5-dimethyl celecoxib. In precision-cut human lung slices, constriction of airways by histamine was significantly reduced in the presence of flupirtine. Kv7 currents in both guinea pig and human ASMCs were inhibited by the Kv7 channel blocker XE991. In human lung slices, XE991 induced robust airway constriction, which was completely reversed by addition of the calcium channel blocker verapamil. These findings suggest that Kv7 channels in ASMCs play an essential role in the regulation of airway diameter and may be targeted pharmacologically to relieve airway hyperconstriction induced by elevated concentrations of bronchoconstrictor agonists.