Su Suwen, Ohno Yukihiro, Lossin Christoph, Hibino Hiroshi, Inanobe Atsushi, Kurachi Yoshihisa
Division of Molecular and Cellular Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
J Pharmacol Exp Ther. 2007 Feb;320(2):573-80. doi: 10.1124/jpet.106.112094. Epub 2006 Oct 27.
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 microM) 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 microM 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.
内向整流钾离子（K(+)）通道Kir4.1负责星形胶质细胞对K(+)的缓冲作用。我们使用全细胞膜片钳技术，研究了三环类抗抑郁药（TCA）去甲替林对在HEK293T细胞中异源表达的Kir4.1通道电流的影响。去甲替林（3 - 300 microM）以浓度依赖性方式可逆地抑制Kir4.1电流，而对神经元Kir2.1电流影响较小。去甲替林对Kir4.1通道的抑制作用取决于与K(+)平衡电位（E(K)）的电压差，在更正电位时效力更强。药物的阻断动力学可用一级动力学描述，随着膜去极化，药物解离减慢而结合加速。在E(K)时，去甲替林对Kir4.1抑制的解离常数（K(d)）为28.1 microM。其他三环类抗抑郁药，如阿米替林、地昔帕明和丙咪嗪，也以类似的电压依赖性方式抑制Kir4.1电流。本研究首次表明，去甲替林及相关三环类抗抑郁药会对星形胶质细胞K(+)缓冲Kir4.1通道产生浓度、电压和时间依赖性抑制，这可能与药物的治疗和/或不良反应有关。
