Interaction of organic cation transporter 3 (SLC22A3) and amphetamine.
Interaction of organic cation transporter 3 (SLC22A3) and amphetamine.
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DOI：
10.1111/j.1471-4159.2010.06738.x
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发表时间：
2010-07
影响因子：
4.7
通讯作者：
Markowitz JS
中科院分区：
文献类型：
--
作者：
Zhu HJ;Appel DI;Gründemann D;Markowitz JS
有机阳离子转运蛋白（OCT）3广泛表达于人体各器官，参与多种外源性和内源性物质的代谢。一些证据表明，在大脑中表达的OCT 3在神经传递的调节中起着重要作用。相对于野生型（WT）动物，Oct 3基因敲除（KO）小鼠表现出改变的行为和神经化学反应的精神兴奋剂，如苯丙胺（AMPH）和甲基苯丙胺。在本研究中，在体外和体内的方法被用来探索潜在的机制，观察到不同的神经药理学作用后，AMPH暴露在Oct 3 KO小鼠。在OCT 3转染细胞中进行的体外摄取研究表明，苯丙胺（d-AMPH）不是OCT 3的底物。然而，OCT 3被确定为神经递质多巴胺（DA）、去甲肾上腺素（NE）和5-羟色胺（5-HT）的高容量和低亲和力转运蛋白。抑制研究表明，d-AMPH对OCT 3介导的DA，NE，5-HT和模型OCT 3底物4-（4-（二甲氨基）苯乙烯基）-N-甲基吡啶碘化物的摄取产生相对较弱的抑制作用。测定的抑制DA和5-HT摄取的IC 50值分别为41.5 ± 7.5和24.1 ± 7.0 μM，而即使使用最高浓度（100 μM）的d-AMPH，也未达到对NE和4-（4-（二甲氨基）苯乙烯基）-N-甲基碘化吡啶摄取的50%抑制。此外，在雄性和雌性Oct 3 KO和WT小鼠中测定了d-AMPH在各种组织中的分布，包括脑、肝、心脏、肾、肌肉、肠、脾、睾丸、子宫和血浆。在所有检测的器官和组织中，未观察到基因型或性别之间的显著差异。我们的研究结果表明，OCT 3是不是一个突出的因素影响的处置d-AMPH。此外，基于体外观察到的抑制效力，d-AMPH不太可能抑制脑中OCT 3介导的单胺摄取。在Oct 3 KO和WT小鼠之间观察到的AMPH的不同神经药理学作用似乎是由于KO小鼠中缺乏Oct 3介导的神经递质摄取。
The organic cation transporter (OCT) 3 is widely expressed in various organs in humans, and involved in the disposition of many exogenous and endogenous compounds. Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission. Relative to wild-type (WT) animals, Oct3 knockout (KO) mice have displayed altered behavioral and neurochemical responses to psychostimulants such as amphetamine (AMPH) and methamphetamine. In the present study, both in vitro and in vivo approaches were utilized to explore potential mechanisms underlying the disparate neuropharmacological effects observed following AMPH exposure in Oct3 KO mice. In vitro uptake studies conducted in OCT3 transfected cells indicated that dextroamphetamine (d-AMPH) is not a substrate of OCT3. However, OCT3 was determined to be a high-capacity and low-affinity transporter for the neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT). Inhibition studies demonstrated that d-AMPH exerts relatively weak inhibitory effects on the OCT3-mediated uptake of DA, NE, 5-HT, and the model OCT3 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide. The IC50 values were determined to be 41.5 ± 7.5 and 24.1 ± 7.0 μM for inhibiting DA and 5-HT uptake, respectively, while 50% inhibition of NE and 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide uptake was not achieved by even the highest concentration of d-AMPH applied (100 μM). Furthermore, the disposition of d-AMPH in various tissues including the brain, liver, heart, kidney, muscle, intestine, spleen, testis, uterus, and plasma were determined in both male and female Oct3 KO and WT mice. No significant difference was observed between either genotypes or sex in all tested organs and tissues. Our findings suggest that OCT3 is not a prominent factor influencing the disposition of d-AMPH. Additionally, based upon the inhibitory potency observed in vitro, d-AMPH is unlikely to inhibit the uptake of monoamines mediated by OCT3 in the brain. Differentiated neuropharmacological effects of AMPHs noted between Oct3 KO and WT mice appear to be due to the absence of Oct3 mediated uptake of neurotransmitters in the KO mice.
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DOI：
10.1111/j.1530-0277.2006.00215.x
发表时间：
2006-10-01
影响因子：
3.2
作者：
Aoyama, Nagisa;Takahashi, Nagahide;Ozaki, Norio
通讯作者：
Ozaki, Norio
影响因子：
2.9
作者：
Nakayama, Hironao;Kitaichi, Kiyoyuki;Hasegawa, Takaaki
通讯作者：
Hasegawa, Takaaki
DOI：
10.1073/pnas.0800466105
发表时间：
2008-12-02
影响因子：
11.1
作者：
Baganz, Nicole L.;Horton, Rebecca E.;Daws, Lynette C.
通讯作者：
Daws, Lynette C.
影响因子：
2.9
作者：
NAOI, M;TAKAHASHI, T;NAGATSU, T
通讯作者：
NAGATSU, T
影响因子：
4.8
作者：
Wu, X;Kekuda, R;Ganapathy, V
通讯作者：
Ganapathy, V