Li Xian-Tao, Li Xiao-Qing, Hu Xi-Mu, Qiu Xiao-Yue
Department of Neuroscience, College of Life Sciences, South-Central University for Nationalities, Wuhan, China.
South-Central University for Nationalities, Wuhan, China.
PLoS One. 2015 Apr 20;10(4):e0124602. doi: 10.1371/journal.pone.0124602. eCollection 2015.
It is well documented that nifedipine, a commonly used dihydropyridine Ca2+ channel blocker, has also significant interactions with voltage-gated K+ (Kv) channels. But to date, little is known whether nifedipine exerted an action on Kv2.1 channels, a member of the Shab subfamily with slow inactivation. In the present study, we explored the effects of nifedipine on rat Kv2.1 channels expressed in HEK293 cells. Data from whole-cell recording showed that nifedipine substantially reduced Kv2.1 currents with the IC50 value of 37.5 ± 5.7 μM and delayed the time course of activation without effects on the activation curve. Moreover, this drug also significantly shortened the duration of inactivation and deactivation of Kv2.1 currents in a voltage-dependent manner. Interestingly, the half-maximum inactivation potential (V1/2) of Kv2.1 currents was -11.4 ± 0.9 mV in control and became -38.5 ± 0.4 mV after application of 50 μM nifedipine. The large hyperpolarizing shift (27 mV) of the inactivation curve has not been reported previously and may result in more inactivation for outward delayed rectifier K+ currents mediated by Kv2.1 channels at repolarization phases. The Y380R mutant significantly increased the binding affinity of nifedipine to Kv2.1 channels, suggesting an interaction of nifedipine with the outer mouth region of this channel. The data present here will be helpful to understand the diverse effects exerted by nifedipine on various Kv channels.
硝苯地平是一种常用的二氢吡啶类钙离子通道阻滞剂，有文献充分证明其与电压门控钾离子（Kv）通道也存在显著相互作用。但迄今为止，对于硝苯地平是否作用于Kv2.1通道（Shab亚家族中具有缓慢失活特性的一个成员）尚知之甚少。在本研究中，我们探究了硝苯地平对在HEK293细胞中表达的大鼠Kv2.1通道的影响。全细胞记录数据显示，硝苯地平显著降低Kv2.1电流，IC50值为37.5±5.7μM，且延迟激活时程，而对激活曲线无影响。此外，该药物还以电压依赖方式显著缩短Kv2.1电流的失活和去激活持续时间。有趣的是，Kv2.1电流的半数最大失活电位（V1/2）在对照时为-11.4±0.9mV，在应用50μM硝苯地平后变为-38.5±0.4mV。失活曲线的大幅超极化移位（27mV）此前未见报道，可能导致在复极化阶段由Kv2.1通道介导的外向延迟整流钾电流更多地失活。Y380R突变体显著增加了硝苯地平与Kv2.1通道的结合亲和力，表明硝苯地平与该通道的外口区域存在相互作用。此处呈现的数据将有助于理解硝苯地平对各种Kv通道产生的多种效应。
