Deletion of SHATI/NAT8L increases dopamine D1 receptor on the cell surface in the nucleus accumbens, accelerating methamphetamine dependence.
Deletion of SHATI/NAT8L increases dopamine D1 receptor on the cell surface in the nucleus accumbens, accelerating methamphetamine dependence.
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DOI：
10.1017/s1461145713001302
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发表时间：
2014-03
期刊：
影响因子：
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通讯作者：
K. Toriumi;Mizuki Kondo;T. Nagai;R. Hashimoto;K. Ohi;Ziyu Song;Junko Tanaka;A. Mouri;T. Koseki;H. Yamamori;Yoko Furukawa-Hibi;T. Mamiya;T. Fukushima;M. Takeda;A. Nitta;Kiyofumi Yamada;T. Nabeshima
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作者：
K. Toriumi;Mizuki Kondo;T. Nagai;R. Hashimoto;K. Ohi;Ziyu Song;Junko Tanaka;A. Mouri;T. Koseki;H. Yamamori;Yoko Furukawa-Hibi;T. Mamiya;T. Fukushima;M. Takeda;A. Nitta;Kiyofumi Yamada;T. Nabeshima
在以前的报告中，我们确定了一种新的分子，SHATI/NAT 8L，对甲基苯丙胺（METH）诱导的过度运动，致敏和条件性位置偏爱（CPP）具有抑制作用。SHATI/NAT 8L通过促进质膜和囊泡多巴胺摄取来减弱中脑核（NAc）中多巴胺溢出的MET诱导的增加。然而，该蛋白的生物学功能仍不清楚。在这项研究中，我们探讨了NAT 8L结合蛋白使用下拉分析，并确定了一些组件的衔接蛋白（AP）-2复合物，这是一个多聚体蛋白定位于质膜的功能，内化货物在网格蛋白介导的内吞作用。为了研究NAT 8L是否调节受体定位到细胞表面，定量NAT 8L敲除（KO）小鼠的NAc中的细胞表面多巴胺D1受体。我们发现与野生型（WT）动物相比，Nat 81 KO小鼠的NAc中细胞表面上的多巴胺D1受体增加。与这一发现一致，与WT小鼠相比，Nat 81 KO小鼠显示出更高的基础运动活性和对D1激动剂的敏感性提高。此外，在Nat 81 KO小鼠中，MET诱导的致敏作用和CPP增强。这些结果表明，NAT 8L可能调节细胞表面多巴胺D1受体的定位，从而控制基础行为和对METH的敏感性。此外，我们观察到一个单核苷酸多态性（SNP）在人类NAT 8L基因相关的奖励依赖，人格特质，在健康受试者的尾状核灰质体积，这表明NAT 8L也可能影响人类的个性。
In a previous report, we identified a novel molecule, SHATI/NAT8L, having an inhibitory effect on methamphetamine (METH)-induced hyperlocomotion, sensitization, and conditioned place preference (CPP). SHATI/NAT8L attenuates the METH-induced increase in dopamine overflow in the nucleus accumbens (NAc) by promoting plasmalemmal and vesicular dopamine uptake. However, the biological functions of the protein remain unclear. In this study, we explored NAT8L-binding proteins using pull-down assays and identified a number of components of the adaptor protein (AP)-2 complex, which is a multimeric protein localized to the plasma membrane that functions to internalize cargo during clathrin-mediated endocytosis. To investigate whether NAT8L regulates the receptor localization to the cell surface, cell-surface dopamine D1 receptor in the NAc of Nat8l knockout (KO) mice was quantified. We found that dopamine D1 receptor on the cell surface was increased in the NAc of Nat8l KO mice compared with the wild type (WT) animals. Consistent with this finding, Nat8l KO mice showed higher basal locomotor activity and heightened sensitivity to D1 agonist compared with WT mice. In addition, METH-induced sensitization and CPP were enhanced in Nat8l KO mice. These results suggest that NAT8L might regulate the localization of cell-surface dopamine D1 receptor, thereby controlling basal behaviour and sensitivity to METH. Furthermore, we observed a single nucleotide polymorphism (SNP) in the human NAT8L gene related to reward dependence, a personality trait, and grey matter volume in the caudate nucleus in healthy subjects, suggesting that NAT8L might also affect human personality.