Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease.
Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease.
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DOI：
10.1111/ejn.13357
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Miller GW
中科院分区：
文献类型：
--
作者：
Lohr KM;Masoud ST;Salahpour A;Miller GW
50多年前，多巴胺首次被确定为定位于中脑的神经递质。多巴胺转运蛋白（DAT; SLC 6A 3）和囊泡单胺转运体2（VMAT 2; SLC 18 A2）是突触前神经元中多巴胺稳态的两种调节剂。DAT将多巴胺从细胞外间隙转运到突触前末梢的胞质溶胶中。VMAT 2然后将这种胞质多巴胺包装到囊泡隔室中，用于随后在神经传递时释放。因此，DAT和VMAT 2协同作用，以有效地在整个神经元中移动发射器。多巴胺在神经元胞质溶胶中的积累可引发氧化应激和神经毒性，表明多巴胺的适当区室化对于神经元功能和疾病风险至关重要。几十年来，研究已经检查了小鼠中转运蛋白功能降低的影响（例如DAT-KO、VMAT 2-KO、VMAT 2缺陷）。然而，我们最近才能够使用BAC转基因方法（DAT-tg，VMAT 2-HI小鼠）评估升高的转运蛋白表达的影响。补充体外工作和神经化学技术来评估多巴胺区室化，一个新的重点转运蛋白作为人类疾病和潜在的药物靶点模型的重要性已经出现。在这里，我们回顾DAT和VMAT 2功能的神经元多巴胺的微妙平衡的重要性。
Dopamine was first identified as a neurotransmitter localized to the midbrain over 50 years ago. The dopamine transporter (DAT; SLC6A3) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2) are two regulators of dopamine homeostasis in the presynaptic neuron. DAT transports dopamine from the extracellular space into the cytosol of the presynaptic terminal. VMAT2 then packages this cytosolic dopamine into vesicular compartments for subsequent release upon neurotransmission. Thus, DAT and VMAT2 act in concert to move transmitter efficiently throughout the neuron. The accumulation of dopamine in the neuronal cytosol can trigger oxidative stress and neurotoxicity, suggesting that the proper compartmentalization of dopamine is critical for neuron function and risk of disease. For decades, studies have examined the effects of reduced transporter function in mice (e.g. DAT-KO, VMAT2-KO, VMAT2-deficient). However, we have only recently been able to assess the effects of elevated transporter expression using BAC transgenic methods (DAT-tg, VMAT2-HI mice). Complemented with in vitro work and neurochemical techniques to assess dopamine compartmentalization, a new focus on the importance of transporter proteins as both models of human disease and potential drug targets has emerged. Here we review the importance of DAT and VMAT2 function in the delicate balance of neuronal dopamine.
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