Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons.
Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons.
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DOI：
10.1016/j.neuron.2014.05.043
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发表时间：
2014-07-16
期刊：
影响因子：
16.2
通讯作者：
Amara SG
中科院分区：
文献类型：
--
作者：
Underhill SM;Wheeler DS;Li M;Watts SD;Ingram SL;Amara SG
安非他明通过通常归因于其调节细胞外多巴胺浓度的能力的机制来改变大脑和改变行为。然而，安非他明的作用也与多巴胺能信号的适应有关。我们在这里报告，当安非他明通过多巴胺转运蛋白进入多巴胺神经元，它刺激兴奋性氨基酸转运蛋白，EAAT 3，在体外和体内多巴胺神经元的内吞作用。与表面EAAT 3的这种减少一致，安非他明增强多巴胺神经元中的兴奋性突触反应。我们还表明，内化的过程是动力蛋白和Rho介导的，需要在EAAT 3的胞质C-末端的独特序列。将基于该基序的肽引入多巴胺神经元可阻断苯丙胺对EAAT 3内化及其对兴奋性反应的作用。这些数据表明，由安非他明触发的EAAT 3的内化增加了多巴胺能信号传导，从而有助于安非他明对神经传递的影响。
Amphetamines modify the brain and alter behavior through mechanisms generally attributed to their ability to regulate extracellular dopamine concentrations. However, the actions of amphetamine are also linked to adaptations in glutamatergic signaling. We report here that when amphetamine enters dopamine neurons through the dopamine transporter, it stimulates endocytosis of an excitatory amino acid transporter, EAAT3, in dopamine neurons in vitro and in vivo. Consistent with this decrease in surface EAAT3, amphetamine potentiates excitatory synaptic responses in dopamine neurons. We also show that the process of internalization is dynamin- and Rho-mediated and requires a unique sequence in the cytosolic C-terminus of EAAT3. Introduction of a peptide based on this motif into dopamine neurons blocks the effects of amphetamine on EAAT3 internalization and its action on excitatory responses. These data indicate that the internalization of EAAT3 triggered by amphetamine increases glutamatergic signaling and thus contributes to the effects of amphetamine on neurotransmission.
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