Upregulation of gamma-aminobutyric acid transporter expression: role of alkylated gamma-aminobutyric acid derivatives.
Upregulation of gamma-aminobutyric acid transporter expression: role of alkylated gamma-aminobutyric acid derivatives.
复制标题
γ-氨基丁酸转运蛋白表达的上调：烷基化γ-氨基丁酸衍生物的作用。
DOI：
10.1042/0300-5127:0290736
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发表时间：
2001
影响因子：
3.9
通讯作者：
Quick,MW
中科院分区：
文献类型：
--
作者：
Whitworth,TL;Quick,MW
普瑞巴林[（S）-（+）-3-异丁基gaba]和加巴喷丁[1-（氨甲基）环己烷乙酸]是γ-氨基丁酸（GABA）衍生物，可有效治疗行为障碍、惊厥、癫痫和痛觉过敏。这些化合物在大脑中的不同作用的机制尚未得到很好的阐明。为了验证这些化合物对大脑中GABA能系统产生影响的假设，我们研究了它们在调节大鼠大脑GABA转运蛋白GAT 1（一种参与调节突触递质水平的质膜蛋白）中的作用。长时间孵育海马培养物，内源性表达GAT 1，加巴喷丁和普瑞巴林引起随后的GABA摄取增加2倍，这是浓度和时间依赖性的。这种摄取的增加与GAT 1蛋白从细胞内位置到质膜的再分布相关。进一步的实验还表明，调节普瑞巴林介导的GAT 1再分布的信号转导级联可能涉及由特定GAT 1底物和拮抗剂激活的途径，但不涉及蛋白激酶C和酪氨酸激酶，这两种已知调节GAT 1再分布的其他途径。这些数据表明，普瑞巴林和加巴喷丁可能通过改变GABA能信号在大脑中发挥其某些作用。
Pregabalin [(S)-(+)-3-isobutylgaba] and gabapentin [1-(aminomethyl)cyclohexane acetic acid] are γ-aminobutyric acid (GABA) derivatives that are effective in the treatment of behavioural disorders, convulsions, epilepsy and hyperalgesia. The mechanisms underlying the diverse actions of these compounds in the brain have not been well elucidated. To test the hypothesis that these compounds exert some of their effects on GABA-ergic systems in the brain, we examined their role in regulating the rat brain GABA transporter GAT1, a plasma membrane protein involved in regulating synaptic transmitter levels. Prolonged incubation of hippocampal cultures, which endogenously express GAT1, with gabapentin and pregabalin caused a 2-fold increase in subsequent GABA uptake, which was concentration- and time-dependent. This increase in uptake was correlated with a redistribution of GAT1 protein from intracellular locations to the plasma membrane. Further experiments also suggested that the signal transduction cascade that modulates pregabalin-mediated GAT1 redistribution may involve pathways activated by specific GAT1 substrates and antagonists but does not involve protein kinase C and tyrosine kinases, two other pathways known to regulate GAT1 redistribution. These data suggest that pregabalin and gabapentin may exert some of their actions in the brain by altering GABAergic signalling.