Inhibition of astroglial inwardly rectifying Kir4.1 channels by a tricyclic antidepressant, nortriptyline
Inhibition of astroglial inwardly rectifying Kir4.1 channels by a tricyclic antidepressant, nortriptyline
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DOI：
10.1124/jpet.106.112094
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发表时间：
2007-02-01
影响因子：
3.5
通讯作者：
Kurachi, Yoshihisa
中科院分区：
文献类型：
--
作者：
Su, Suwen;Ohno, Yukihiro;Kurachi, Yoshihisa
内向整流K+通道Kir4.1负责星形胶质细胞的K+缓冲。我们研究了去甲替林，三环类抗抑郁药（TCA），在HEK 293 T细胞异源表达的Kir4.1通道电流的影响，使用全细胞膜片钳技术。去甲替林（3 - 300 μ M）以浓度依赖性方式可逆地抑制Kir4.1电流，而它轻微地影响神经元Kir2.1电流. Kir4.1通道的抑制依赖于去甲替林的电压差从K+平衡电位（E K），具有更大的效力，在更积极的电位。药物的阻断动力学可用一级动力学描述，其中药物的解离减慢，并且随着膜去极化而缔合加速。去甲替林抑制Kir4.1的解离常数（Kd）在E-K时为28.1 μ M。其他TCA，如阿米替林，地昔帕明，丙咪嗪，也抑制Kir4.1电流以类似的电压依赖性方式。这项研究首次表明，去甲替林和相关的TCAs引起星形胶质细胞K+缓冲Kir4.1通道的浓度，电压和时间依赖性抑制，这可能涉及药物的治疗和/或不良反应。
The inwardly rectifying K+ ( Kir) channel Kir4.1 is responsible for astroglial K+ buffering. We examined the effects of nortriptyline, a tricyclic antidepressant ( TCA), on Kir4.1 channel currents heterologously expressed in HEK293T cells, using a whole-cell patch-clamp technique. Nortriptyline ( 3 - 300 mu M) reversibly inhibited Kir4.1 currents in a concentration- dependent manner, whereas it marginally affected neuronal Kir2.1 currents. The inhibition of Kir4.1 channels by nortriptyline depended on the voltage difference from the K+ equilibrium potential ( E K), with greater potency at more positive potentials. Blocking kinetics of the drug could be described by first-order kinetics, where dissociation of the drug slowed down and association accelerated as the membrane was depolarized. The dissociation constant ( K-d) of nortriptyline for Kir4.1 inhibition was 28.1 mu M at E-K. Other TCAs, such as amitriptyline, desipramine, and imipramine, also inhibited Kir4.1 currents in a similar voltage-dependent fashion. This study shows for the first time that nortriptyline and related TCAs cause a concentration-, voltage-, and time-dependent inhibition of astroglial K+- buffering Kir4.1 channels, which might be involved in therapeutic and/or adverse actions of the drugs.