Decreased vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) function in knockout mice affects aging of dopaminergic systems.
Decreased vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) function in knockout mice affects aging of dopaminergic systems.
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DOI：
10.1016/j.neuropharm.2013.07.031
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发表时间：
2014-01
影响因子：
4.7
通讯作者：
Uhl GR
中科院分区：
文献类型：
--
作者：
Hall FS;Itokawa K;Schmitt A;Moessner R;Sora I;Lesch KP;Uhl GR
多巴胺（DA）通过多巴胺转运蛋白（DAT; SLC 3A 6）和囊泡单胺转运蛋白2（VMAT 2; SLC 18 A2）蓄积和区室化。这些转运蛋白分别作用于多巴胺能神经元的质膜和囊泡膜，从而调节包括囊泡外细胞质区室的神经元区室中的DA水平。已经假设该隔室中的DA有助于氧化损伤，其可以降低衰老大脑中多巴胺能神经元的功能，并且可能有助于减少在老年动物中发现的多巴胺能神经化学标记物、运动行为和对多巴胺能药物的反应。本文报道的研究检查了VMAT 2或DAT杂合缺失的老年小鼠，其各自将转运蛋白表达降低至野生型（WT）小鼠中发现的水平的约50%。老年小鼠在各种情况下表现出减少的运动反应，包括对运动兴奋剂的反应，以及单胺水平和代谢物以区域依赖性方式的变化。衰老的几种影响在杂合VMAT 2基因敲除（KO）小鼠中更加明显，包括衰老诱导的运动减少和对可卡因的运动反应减少。相比之下，在杂合DAT KO小鼠中，衰老的一些影响减少或未观察到。这些发现支持了DAT和VMAT 2表达改变影响多巴胺能功能的年龄相关变化的观点。这些影响最有可能介导的DA区室化的改变，并可能被假设为更加剧的其他因素，影响细胞溶质DA的代谢。
Dopamine (DA) is accumulated and compartmentalized by the dopamine transporter (DAT; SLC3A6) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2). These transporters work at the plasma and vesicular membranes of dopaminergic neurons, respectively, and thus regulate levels of DA in neuronal compartments that include the extravesicular cytoplasmic compartment. DA in this compartment has been hypothesized to contribute to oxidative damage that can reduce the function of dopaminergic neurons in aging brains and may contribute to reductions in dopaminergic neurochemical markers, locomotor behavior and responses to dopaminergic drugs that are found in aged animals. The studies reported here examined aged mice with heterozygous deletions of VMAT2 or of DAT, which each reduce transporter expression to about 50% of levels found in wild-type (WT) mice. Aged mice displayed reduced locomotor responses under a variety of circumstances, including in response to locomotor stimulants, as well as changes in monoamine levels and metabolites in a regionally dependent manner. Several effects of aging were more pronounced in heterozygous VMAT2 knockout (KO) mice, including aging induced reductions in locomotion and reduced locomotor responses to cocaine. By contrast, some effects of aging were reduced or not observed in heterozygous DAT KO mice. These findings support the idea that altered DAT and VMAT2 expression affect age-related changes in dopaminergic function. These effects are most likely mediated by alterations in DA compartmentalization, and might be hypothesized to be more exacerbated by other factors that affect the metabolism of cytosolic DA.
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