Characterization of murine polyspecific monoamine transporters.
Characterization of murine polyspecific monoamine transporters.
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DOI：
10.1002/2211-5463.12183
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发表时间：
2017-02
期刊：
影响因子：
2.6
通讯作者：
Yanai K
中科院分区：
文献类型：
--
作者：
Miura Y;Yoshikawa T;Naganuma F;Nakamura T;Iida T;Kárpáti A;Matsuzawa T;Mogi A;Harada R;Yanai K
中枢神经系统单胺清除的失调存在于多种神经精神障碍中，近年来的研究日益强调多特异性单胺转运体在单胺清除中的作用。然而，到目前为止，还没有研究正确地表征小鼠大脑中的多特异性单胺转运体。在本研究中，我们研究了三种小鼠多特异性单胺转运体[有机阳离子转运体2(Oct2)、Oct3和质膜单胺转运体(PmAt)]的动力学特性，并比较了这些转运体在不同脑区的绝对mRNA表达水平。首先，我们评估了每个转运体对去甲肾上腺素、多巴胺、5-羟色胺和组胺的亲和力，发现小鼠的同源底物亲和力与人类同源底物的亲和力相似。接下来，我们进行了药物抑制试验，并确定了多特异性单胺转运体的药理特性的物种间差异；特别是皮质酮和Decynium-22，这两种被广泛认为是典型的人类Oct3抑制剂，增强了小鼠Oct3的转运活性。最后，我们量化了每种转运蛋白在小鼠大脑不同区域的绝对mRNA表达水平，发现虽然所有三种转运蛋白都普遍表达，但pmAt是表达最高的转运蛋白。这些结果为未来研究多特异性单胺转运体在神经和神经精神疾病中的作用提供了重要的基础。
The dysregulation of monoamine clearance in the central nervous system occurs in various neuropsychiatric disorders, and the role of polyspecific monoamine transporters in monoamine clearance is increasingly highlighted in recent studies. However, no study to date has properly characterized polyspecific monoamine transporters in the mouse brain. In the present study, we examined the kinetic properties of three mouse polyspecific monoamine transporters [organic cation transporter 2 (Oct2), Oct3, and plasma membrane monoamine transporter (Pmat)] and compared the absolute mRNA expression levels of these transporters in various brain areas. First, we evaluated the affinities of each transporter for noradrenaline, dopamine, serotonin, and histamine, and found that mouse ortholog substrate affinities were similar to those of human orthologs. Next, we performed drug inhibition assays and identified interspecies differences in the pharmacological properties of polyspecific monoamine transporters; in particular, corticosterone and decynium‐22, which are widely recognized as typical inhibitors of human OCT3, enhanced the transport activity of mouse Oct3. Finally, we quantified absolute mRNA expression levels of each transporter in various regions of the mouse brain and found that while all three transporters were ubiquitously expressed, Pmat was the most highly expressed transporter. These results provide an important foundation for future translational research investigating the roles of polyspecific monoamine transporters in neurological and neuropsychiatric disease.