State-dependent block of wild-type and inactivation-deficient Na+ channels by flecainide.
State-dependent block of wild-type and inactivation-deficient Na+ channels by flecainide.
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DOI：
10.1085/jgp.200308857
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发表时间：
2003-09
期刊：
影响因子：
--
通讯作者：
Wang SY
中科院分区：
文献类型：
--
作者：
Wang GK;Russell C;Wang SY
抗抑郁药氟卡尼似乎对疼痛性先天性肌强直和LQT-3/ΔKPQ综合征有益。这两种疾病都表现出骨骼肌或心肌细胞中小但持续的晚期Na+电流。因此，氟卡尼可以阻断晚期Na+电流以发挥其功效。为了研究这种可能性，我们在Hek 293 t细胞中表达β1亚基的野生型和失活缺陷型rNav1.4肌肉Na+通道（L435 W/L437 C/A438 W）中表征了氟卡尼的状态依赖性阻断。对于野生型Na+通道，-140 mV时的氟卡尼静息阻滞较弱，当细胞未受刺激1，000 s时，估计50%抑制浓度（IC 50）为365 μM。然而，在100 μM氟卡尼下，以低至每60 s 1次的频率施加+30 mV的短暂监测脉冲，可产生约70%的使用依赖性Na+峰电流阻断。从这种使用依赖性阻滞中恢复遵循指数函数，在−140 mV下的时间常数超过225 s。失活的野生型Na+通道与氟卡尼在−50 mV下也缓慢相互作用，时间常数为7.9 s。与此相反，氟卡尼阻断失活缺陷型Na+通道的开放状态有力揭示了其快速的时间依赖性阻滞晚Na+电流。在+30 mV时，氟卡尼开放通道阻滞的IC 50为0.61 μM，正好在治疗血浆浓度范围内;结合速率和解离速率常数分别为14.9 μM− 1 s −1和12.2 s−1。复极化至−140 mV时，失活缺陷型Na+通道的氟卡尼阻滞恢复，时间常数为11.2 s，比野生型快20倍。我们得出结论，氟卡尼直接阻断持续性晚Na+电流具有高亲和力。快速失活门，可能通过其S6对接位点，可以进一步稳定野生型Na+通道中的氟卡尼-受体复合物。
The antiarrhythmic agent flecainide appears beneficial for painful congenital myotonia and LQT-3/ΔKPQ syndrome. Both diseases manifest small but persistent late Na+ currents in skeletal or cardiac myocytes. Flecainide may therefore block late Na+ currents for its efficacy. To investigate this possibility, we characterized state-dependent block of flecainide in wild-type and inactivation-deficient rNav1.4 muscle Na+ channels (L435W/L437C/A438W) expressed with β1 subunits in Hek293t cells. The flecainide-resting block at −140 mV was weak for wild-type Na+ channels, with an estimated 50% inhibitory concentration (IC50) of 365 μM when the cell was not stimulated for 1,000 s. At 100 μM flecainide, brief monitoring pulses of +30 mV applied at frequencies as low as 1 per 60 s, however, produced an ∼70% use-dependent block of peak Na+ currents. Recovery from this use-dependent block followed an exponential function, with a time constant over 225 s at −140 mV. Inactivated wild-type Na+ channels interacted with flecainide also slowly at −50 mV, with a time constant of 7.9 s. In contrast, flecainide blocked the open state of inactivation-deficient Na+ channels potently as revealed by its rapid time-dependent block of late Na+ currents. The IC50 for flecainide open-channel block at +30 mV was 0.61 μM, right within the therapeutic plasma concentration range; on-rate and off-rate constants were 14.9 μM−1s−1 and 12.2 s−1, respectively. Upon repolarization to −140 mV, flecainide block of inactivation-deficient Na+ channels recovered, with a time constant of 11.2 s, which was ∼20-fold faster than that of wild-type counterparts. We conclude that flecainide directly blocks persistent late Na+ currents with a high affinity. The fast-inactivation gate, probably via its S6 docking site, may further stabilize the flecainide-receptor complex in wild-type Na+ channels.
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影响因子：
4.8
作者：
MCPHEE, JC;RAGSDALE, DS;CATTERALL, WA
通讯作者：
CATTERALL, WA
DOI：
10.1073/pnas.89.22.10910
发表时间：
1992-11-15
影响因子：
11.1
作者：
WEST, JW;PATTON, DE;CATTERALL, WA
通讯作者：
CATTERALL, WA
影响因子：
3.4
作者：
Wang, SY;Bonner, K;Wang, GK
通讯作者：
Wang, GK
影响因子：
3.8
作者：
Liu, Huajun;Tateyama, Michihiro;Clancy, Colleen E;Abriel, Hugues;Kass, Robert S
通讯作者：
Kass, Robert S
DOI：
10.1085/jgp.20028723
发表时间：
2003-03
期刊：
The Journal of general physiology
影响因子：
--
作者：
Liu H;Atkins J;Kass RS
通讯作者：
Kass RS