Hyperdopaminergic modulation of inhibitory transmission is dependent on GSK-3β signaling-mediated trafficking of GABAA receptors.
Hyperdopaminergic modulation of inhibitory transmission is dependent on GSK-3β signaling-mediated trafficking of GABAA receptors.
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DOI：
10.1111/j.1471-4159.2012.07790.x
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发表时间：
2012-07
影响因子：
4.7
通讯作者：
Gao WJ
中科院分区：
文献类型：
--
作者：
Li YC;Wang MJ;Gao WJ
γ-氨基丁酸（GABA）系统的皮质多巴胺（DA）调节与认知功能和精神障碍密切相关。我们最近报道，糖原合成酶激酶3β（GSK-3β）通路是前额叶皮层高多巴胺/D2受体介导的NMDA受体抑制所必需的。在这里，我们探讨GSK-3β是否也参与GABAA受体介导的抑制性传递的多巴胺能调节。我们证实，DA诱导剂量依赖性，双向调节抑制性突触后电流（IPSC）在前额叶神经元。GSK-3β抑制剂与不同剂量DA联合应用对DA的调节作用不同，GSK-3β抑制剂完全阻断高剂量（20 μM）DA对IPSC的抑制作用，但对低剂量（200 nM）DA对IPSC的易化调节作用有限。我们还证实，DA应用于培养的前额叶神经元和在体给予DA再摄取抑制剂可显著降低GABAA受体β2/3亚基的表面表达。这些作用可通过预先给予GSK-3β抑制剂而阻断。我们探讨了DA介导的GABAA受体运输的调节，并表现出布雷菲德菌素A抑制的GDP/GTP交换因子2（BIG 2）或GABAA受体的动力蛋白依赖性运输的参与。总之，这些数据表明，DA可能通过不同的信号通路影响突触抑制，这取决于浓度。GSK-3β信号通路参与DA诱导的BIG 2依赖性插入的减少和GABAA受体的动力蛋白依赖性内化的增加，这导致抑制性突触传递的抑制。
Cortical dopamine (DA) modulation of the gamma-amino butyric acid (GABA) system is closely associated with cognitive function and psychiatric disorders. We recently reported that the glycogen synthase kinase 3β (GSK-3β) pathway is required for hyperdopamine/D2 receptor-mediated inhibition of NMDA receptors in the prefrontal cortex. Here we explore whether GSK-3β is also involved in dopaminergic modulation of GABAA receptor-mediated inhibitory transmission. We confirmed that DA induces a dose-dependent, bidirectional regulatory effect on inhibitory postsynaptic currents (IPSCs) in prefrontal neurons. The modulatory effects of DA were differentially affected by co-application of GSK-3β inhibitors and different doses of DA. GSK-3β inhibitors completely blocked high-dose (20 μM) DA-induced depressive effects on IPSCs but exhibited limited effects on the facilitating regulation of IPSC in low-dose DA (200 nM). We also confirmed that surface expressions of GABAA receptor β2/3 subunits were significantly decreased by DA applied in cultured prefrontal neurons and in vivo administration of DA reuptake inhibitor. These effects were blocked by prior administration of GSK-3β inhibitors. We explored DA-mediated regulation of GABAA receptor trafficking and exhibited the participation of brefeldin A-inhibited GDP/GTP exchange factor 2 (BIG2) or dynamin-dependent trafficking of GABAA receptors. Together, these data suggest that DA may act through different signaling pathways to affect synaptic inhibition, depending on the concentration. The GSK-3β signaling pathway is involved in DA-induced decrease in BIG2-dependent insertion and an increase in the dynamin- dependent internalization of GABAA receptors, which results in suppression of inhibitory synaptic transmission.
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影响因子：
30.8
作者：
Emamian, ES;Hall, D;Gogos, JA
通讯作者：
Gogos, JA
影响因子：
5.3
作者：
Hjelmstad, GO
通讯作者：
Hjelmstad, GO
DOI：
10.1176/appi.ajp.2009.08121873
发表时间：
2010-04
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Freyberg Z;Ferrando SJ;Javitch JA
通讯作者：
Javitch JA
DOI：
10.1073/pnas.0307921101
发表时间：
2004-04-06
影响因子：
11.1
作者：
Beaulieu, JM;Sotnikova, TD;Caron, MG
通讯作者：
Caron, MG
影响因子：
64.8
作者：
CROSS, DAE;ALESSI, DR;HEMMINGS, BA
通讯作者：
HEMMINGS, BA