Inhibitory effects of the antiepileptic drug ethosuximide on G protein-activated inwardly rectifying K+ channels
Inhibitory effects of the antiepileptic drug ethosuximide on G protein-activated inwardly rectifying K+ channels
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DOI：
10.1016/j.neuropharm.2008.10.003
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发表时间：
2009-02-01
影响因子：
4.7
通讯作者：
Ikeda, Kazutaka
中科院分区：
文献类型：
--
作者：
Kobayashi, Toru;Hirai, Hirokazu;Ikeda, Kazutaka
抗癫痫药物通过调节神经元的兴奋性来防止癫痫发作。乙索昔胺被选择性地用于治疗失神性癫痫，并且除了几种抗癫痫药物外，还被证明具有治疗其他几种神经精神疾病的潜力。虽然乙thosuximide抑制t型Ca2+，非失活的Na+和Ca2+激活的K+通道，但乙thosuximide作用的分子机制尚未充分阐明。G蛋白激活的内向纠偏K+通道（GIRK或Kir3）在调节神经元兴奋性、心率和血小板聚集方面发挥重要作用。本研究首先通过非洲爪蟾卵母细胞表达试验研究了各种抗癫痫药物对GIRK通道的影响。临床相关浓度的乙索昔胺可抑制非洲爪蟾卵母细胞中GIRK通道的表达。在每个电压脉冲期间，抑制作用与浓度有关，但与电压无关，与时间无关。然而，其他抗癫痫药物：苯妥英、丙戊酸、卡马西平、苯巴比妥、加巴喷丁、托吡酯和唑尼沙胺，即使在中毒浓度下也对GIRK通道没有显著影响。相比之下，Kir1.1和Kir2.1通道对所有测试的药物都不敏感。乙磺酰亚胺也能减弱乙醇诱导的GIRK电流。当在细胞内施用时，没有观察到这种抑制作用。在小脑颗粒细胞切片中，乙氧亚胺抑制GTP γ s激活的GIRK电流。此外，乙胺可抑制ADP和肾上腺素诱导的血小板聚集。但不是通过charybdotoxin，一种血小板Ca2+激活的K+通道阻滞剂。这些结果提示，乙磺酰亚胺对GIRK通道的抑制作用可能影响部分脑、心脏和血小板功能。(c) 2008 Elsevier Ltd.版权所有。
Antiepileptic drugs protect against seizures by modulating neuronal excitability. Ethosuximide is selectively used for the treatment of absence epilepsy, and has also been shown to have the potential for treating several other neuropsychiatric disorders in addition to several antiepileptic drugs. Although ethosuximide inhibits T-type Ca2+, noninactivating Na+, and Ca2+-activated K+ channels, the molecular mechanisms underlying the effects of ethosuximide have not yet been sufficiently clarified. G protein-activated inwardly rectifying K+ channels (GIRK, or Kir3) play an important role in regulating neuronal excitability, heart rate and platelet aggregation. In the present study, the effects of various antiepileptic drugs on GIRK channels were examined first by using the Xenopus oocyte expression assay. Ethosuximide at clinically relevant concentrations inhibited GIRK channels expressed in Xenopus oocytes. The inhibition was concentration-dependent, but voltage-independent, and time-independent during each voltage pulse. However, the other antiepileptic drugs tested: phenytoin, valproic acid, carbamazepine, phenobarbital, gabapentin, topiramate and zonisamide, had no significant effects on GIRK channels even at toxic concentrations. In contrast, Kir1.1 and Kir2.1 channels were insensitive to all of the drugs tested. Ethosuximide also attenuated ethanol-induced GIRK currents. These inhibitory effects of ethosuximide were not observed when ethosuximide was applied intracellularly. In granule cells of cerebellar slices, ethosuximide inhibited GTP gamma S-activated GIRK currents. Moreover, ADP- and epinephrine-induced platelet aggregation was inhibited by ethosuximide. but not by charybdotoxin, a platelet Ca2+-activated K+ channel blocker. These results suggest that the inhibitory effects of ethosuximide on GIRK channels may affect some of brain, heart and platelet functions. (c) 2008 Elsevier Ltd. All rights reserved.