Interaction of Selective Serotonin Reuptake Inhibitors with Neuronal Nicotinic Acetylcholine Receptors
Interaction of Selective Serotonin Reuptake Inhibitors with Neuronal Nicotinic Acetylcholine Receptors
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DOI：
10.1021/bi100536t
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发表时间：
2010-07-13
期刊：
影响因子：
2.9
通讯作者：
Jozwiak, Krzysztof
中科院分区：
文献类型：
--
作者：
Arias, Hugo R.;Feuerbach, Dominik;Jozwiak, Krzysztof
我们使用 Ca(2+) 流入、放射性配体结合和分子对接方法，比较了氟西汀和帕罗西汀这两种选择性血清素再摄取抑制剂 (SSRI) 与不同构象状态下的人 (h) α 4 β 2、α 3 β 4 和 α 7 烟碱乙酰胆碱受体 (AChR) 的相互作用。结果表明：(1) 氟西汀在抑制 h α 4 β 2 和 h α 7 AChR 上激动剂激活的 Ca(2+) 内流方面比帕罗西汀更有效，而两种 SSRIs 在 h α 3 β 4 AChR 上的效力几乎相同。然而，帕罗西汀对 h α 7 AChR 的作用更有效。 (2) 与静息状态相比，当 AChR 处于脱敏状态时，SSRI 与 [(3)H] 丙咪嗪位点的结合具有更高的亲和力。 (3) 氟西汀的不同受体特异性由其抑制效力或结合亲和力决定，表明当 AChR 处于关闭或激活状态时存在不同的相互作用模式。 (4) 中性和质子化的氟西汀与位于 AChR 离子通道中部的结合域相互作用。总之，SSRIs 通过与三环类抗抑郁药共有的管腔位点结合，抑制最重要的神经元 AChR，其效力和亲和力与临床相关。
We compared the interaction of fluoxetine and paroxetine, two selective serotonin reuptake inhibitors (SSRIs), with the human (h) alpha 4 beta 2, alpha 3 beta 4, and alpha 7 nicotinic acetylcholine receptors (AChRs) in different conformational states, using Ca(2+) influx, radioligand binding, and molecular docking approaches. The results established that (1) fluoxetine was more potent than paroxetine in inhibiting agonist-activated Ca(2+) influx on h alpha 4 beta 2 and h alpha 7 AChRs, whereas the potency of both SSRIs was practically the same in the h alpha 3 beta 4 AChR. However, paroxetine was more potent in the h alpha 7 AChR. (2) SSRIs bind to the [(3)H] imipramine locus with higher affinity when the AChRs are in the desensitized states compared to the resting states. (3) The different receptor specificity for fluoxetine determined by their inhibitory potencies or binding affinities suggests different modes of interaction when the AChR is in the closed or activated state. (4) Neutral and protonated fluoxetine interacts with a binding domain located in the middle of the AChR ion channel. In conclusion, SSRIs inhibit the most important neuronal AChRs with potencies and affinities that are clinically relevant by binding to a luminal site that is shared with tricyclic antidepressants.