Inhibition of G protein-activated inwardly rectifying K+ channels by various antidepressant drugs
Inhibition of G protein-activated inwardly rectifying K+ channels by various antidepressant drugs
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DOI：
10.1038/sj.npp.1300484
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发表时间：
2004-10-01
影响因子：
7.6
通讯作者：
Ikeda, K
中科院分区：
文献类型：
--
作者：
Kobayashi, T;Washiyama, K;Ikeda, K
G蛋白激活的内向纠偏K+通道（GIRK，也称为Kir3）被各种G蛋白偶联受体激活。GIRK通道在大多数脑区神经元兴奋性和心率的抑制调节中起重要作用。调节GIRK通道活动可能影响许多脑功能。在这里，我们报道了各种抗抑郁药的抑制作用：丙咪嗪、地西帕明、阿米替林、去甲替林、氯丙咪嗪、马普替林和西酞普兰对GIRK通道的抑制作用。在注射了GIRK1/ GIRK2、GIRK2或GIRK1/ GIRK4亚基mrna的非洲尾蜥卵母细胞中，除了氟伏沙明、齐默利定和安非他酮外，各种抗抑郁药在微摩尔浓度下通过基础GIRK活性可逆地降低了内向电流。抑制作用具有不同程度的效价和有效性，但与电压和时间无关。相比之下，其他Kir亚家族的Kir1.1和Kir2.1通道对所有药物都不敏感。此外，克隆的A(1)腺苷受体激活的GIRK电流反应同样被三环抗抑郁药地西帕明抑制。当地西帕明在细胞内应用时，没有观察到地西帕明的抑制作用，并且不受细胞外pH的影响，这改变了未带电到质子化的地西帕明的比例，表明其从细胞外侧起作用。地西帕明存在时，乙醇诱导的GIRK电流也减弱。我们的研究结果表明，三环类抗抑郁药和马普替林对GIRK通道的抑制可能有助于临床实践中观察到的一些治疗效果和不良副作用，特别是过量服用时的癫痫发作和心房心律失常。
G protein-activated inwardly rectifying K+ channels (GIRK, also known as Kir3) are activated by various G protein-coupled receptors. GIRK channels play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate. Modulation of GIRK channel activity may affect many brain functions. Here, we report the inhibitory effects of various antidepressants: imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, maprotiline, and citalopram, on GIRK channels. In Xenopus oocytes injected with mRNAs for GIRK1/ GIRK2, GIRK2 or GIRK1/ GIRK4 subunits, the various antidepressants tested, except fluvoxamine, zimelidine, and bupropion, reversibly reduced inward currents through the basal GIRK activity at micromolar concentrations. The inhibitions were concentration-dependent with various degrees of potency and effectiveness, but voltage- and time-independent. In contrast, Kir1.1 and Kir2.1 channels in other Kir channel subfamilies were insensitive to all of the drugs. Furthermore, GIRK current responses activated by the cloned A(1) adenosine receptor were similarly inhibited by the tricyclic antidepressant desipramine. The inhibitory effects of desipramine were not observed when desipramine was applied intracellularly, and were not affected by extracellular pH, which changed the proportion of the uncharged to protonated desipramine, suggesting its action from the extracellular side. The GIRK currents induced by ethanol were also attenuated in the presence of desipramine. Our results suggest that inhibition of GIRK channels by the tricyclic antidepressants and maprotiline may contribute to some of the therapeutic effects and adverse side effects, especially seizures and atrial arrhythmias in overdose, observed in clinical practice.