The Inhibitory Effects Of Ca²⁺ Channel Blocker Nifedipine On Rat Kv2.1 Potassium Channels

Kv2.1 is one of voltage-gated potassium channel members,and has a crucial role in the control of electrical signaling and sensitivity in excitable tissue.It is well documented that nifedipine,a commonly used dihydropyridine Ca2+ channel blocker,been used to treat diseases such as hypertension and 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.In the present study,we explored the effects of nifedipine on rat Kv2.1 channels expressed in HEK 293 cells and the underlying mechanism.Data from whole-cell recording showed that nifedipine substantially reduced Kv2.1 currents with the IC50 value of 37.5 ± 5.7 ?M and delayed the time course of activation without effects on the activation curve.The Y380 R mutant significantly increased the binding affinity of nifedipine to Kv2.1 channels with the IC50 value of 15.2 ± 1.3 ?M,suggesting an interaction of nifedipine with the 380 position of this channel.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 ?M nifedipine.The large hyperpolarizing shift(27 mV)of the inactivation curve has not been reported previously.And nifedipine accelerated the recovery rate of Kv2.1.Our data revealed that nifedipine worked in both an open-channel and closed-channel blocking way and the 27 mV shift may result in more inactivation for outward delayed rectifier K+ currents mediated by Kv2.1 channels at repolarization phases.Conclusions:(1)nifedipine reversibly reduced Kv2.1 currents in a dose-and voltage-dependent manners.(2)nefedipine may act on the tyrosine of Kv2.1 position 380.(3)nefedipine produced a 27 mV hyperpolarizing shift of the inactivation curve.