Inhibition of the HERG potassium channel by the tricyclic antidepressant doxepin.
Inhibition of the HERG potassium channel by the tricyclic antidepressant doxepin.
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DOI：
10.1016/j.bcp.2007.04.024
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发表时间：
2007-08-01
影响因子：
5.8
通讯作者：
Hancox, J. C.
中科院分区：
文献类型：
--
作者：
Duncan, R. S.;McPate, M. J.;Ridley, J. M.;Gao, Z.;James, A. F.;Leishman, D. J.;Leaney, J. L.;Witchel, H. J.;Hancox, J. C.
关键词：
HERG（人类ether-à-go-go相关基因）编码负责心脏快速延迟整流钾电流（IKr）的通道。本研究探讨了与QT间期延长和心律失常相关的三环类抗抑郁药多塞平对HERG通道的影响。在37 °C下对重组HERG通道电流（IHERG）和来自兔心室肌细胞的天然IKr“尾”进行全细胞膜片钳记录。多塞平抑制IHERG的IC 50值为6.5 ± 1.4 μM，抑制天然IKr的IC 50值为4.4 ± 0.6 μM。对IHERG的抑制作用在膜去极化后迅速发展，但对电压无显著依赖性，并且对IHERG的电压依赖性动力学几乎没有改变。S631 A和N588 K失活衰减突变（分别位于通道孔和外部S5-孔接头中的残基）均未显著降低抑制效力。S6点突变Y 652 A使IHERG阻断的IC 50增加了10.42倍; F656 A突变体在某些浓度下也减弱了多塞平的作用。HERG通道阻滞可能是多塞平QT间期延长报告病例的基础。值得注意的是，这项研究还确定多塞平作为一种有效的抑制剂突变（N588 K）HERG通道负责变异1的短QT综合征。
HERG (human ether-à-go-go-related gene) encodes channels responsible for the cardiac rapid delayed rectifier potassium current, IKr. This study investigated the effects on HERG channels of doxepin, a tricyclic antidepressant linked to QT interval prolongation and cardiac arrhythmia. Whole-cell patch-clamp recordings were made at 37 °C of recombinant HERG channel current (IHERG), and of native IKr ‘tails’ from rabbit ventricular myocytes. Doxepin inhibited IHERG with an IC50 value of 6.5 ± 1.4 μM and native IKr with an IC50 of 4.4 ± 0.6 μM. The inhibitory effect on IHERG developed rapidly upon membrane depolarization, but with no significant dependence on voltage and with little alteration to the voltage-dependent kinetics of IHERG. Neither the S631A nor N588K inactivation-attenuating mutations (of residues located in the channel pore and external S5-Pore linker, respectively) significantly reduced the potency of inhibition. The S6 point mutation Y652A increased the IC50 for IHERG blockade by ∼4.2-fold; the F656A mutant also attenuated doxepin's action at some concentrations. HERG channel blockade is likely to underpin reported cases of QT interval prolongation with doxepin. Notably, this study also establishes doxepin as an effective inhibitor of mutant (N588K) HERG channels responsible for variant 1 of the short QT syndrome.
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影响因子：
3.6
作者：
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通讯作者：
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影响因子：
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DOI：
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作者：
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通讯作者：
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