Inhibition of G protein-activated inwardly rectifying K+ channels by the antidepressant paroxetine
Inhibition of G protein-activated inwardly rectifying K+ channels by the antidepressant paroxetine
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DOI：
10.1254/jphs.fp0060708
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发表时间：
2006-11-01
影响因子：
3.5
通讯作者：
Ikeda, Kazutaka
中科院分区：
文献类型：
--
作者：
Kobayashi, Toru;Washiyama, Kazuo;Ikeda, Kazutaka
帕罗西汀通常用作选择性5-羟色胺再摄取抑制剂，用于治疗抑郁症和其他精神疾病。然而，帕罗西汀作用的分子机制尚未得到充分阐明。使用爪蟾卵母细胞表达测定，我们研究了帕罗西汀对G蛋白激活的内向整流K+（GIRK）通道的影响，GIRK通道在降低大多数脑区的神经元兴奋性和心率中起着重要作用。在注射了GIRK 1/GIRK 2、GIRK 2或GIRK 1/GIRK 4亚基mRNA的卵母细胞中，帕罗西汀可逆地降低了通过表达的GIRK通道的内向电流。在每个电压脉冲期间，抑制是浓度依赖性的，但不依赖于电压和时间。然而，两种结构不同的抗抑郁药：米那普仑和曲唑酮，只引起了一个小的抑制基础GIRK电流。此外，Kir1.1和Kir2.1通道对所有抗抑郁药均不敏感。此外，GIRK电流诱导的激活A，腺苷受体或乙醇被抑制由细胞外应用帕罗西汀以浓度依赖性的方式，但不受细胞内应用帕罗西汀。我们的研究结果表明，抑制GIRK通道帕罗西汀可能有助于部分其治疗效果和不良副作用。
Paroxetine is commonly used as a selective serotonin reuptake inhibitor for the treatment of depression and other psychiatric disorders. However, the molecular mechanisms of the paroxetine effects have not yet been sufficiently clarified. Using Xenopus oocyte expression assays, we investigated the effects of paroxetine on G protein-activated inwardly rectifying K+ (GIRK) channels, which play an important role in reducing neuronal excitability in most brain regions and the heart rate. In oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, paroxetine reversibly reduced inward currents through the expressed GIRK channels. The inhibition was concentration-dependent, but voltage-independent and time-independent during each voltage pulse. However, two structurally different antidepressants: milnacipran and trazodone, caused only a small inhibition of basal GIRK currents. Additionally, Kir1.1 and Kir2.1 channels were insensitive to all of the antidepressants. Furthermore, the GIRK currents induced by activation of A, adenosine receptors or by ethanol were inhibited by extracellularly applied paroxetine in a concentration-dependent manner, but not affected by intracellularly applied paroxetine. Our results suggest that inhibition of GIRK channels by paroxetine may contribute partly to some of its therapeutic effects and adverse side effects.