Inhibition of uptake, steady-state currents, and transient charge movements generated by the neuronal GABA transporter by various anticonvulsant drugs
Inhibition of uptake, steady-state currents, and transient charge movements generated by the neuronal GABA transporter by various anticonvulsant drugs
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DOI：
10.1038/sj.bjp.0702794
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发表时间：
1999-09-01
影响因子：
7.3
通讯作者：
Schwarz, W
中科院分区：
文献类型：
--
作者：
Eckstein-Ludwig, U;Fei, J;Schwarz, W
1我们在非洲爪蟾卵母细胞中表达了小鼠脑GABA转运蛋白（GAT 1），并通过测量H-3标记的GABA摄取和GAT 1介导的电流，研究了四种抗癫痫药物噻加宾（TGB）、氨己烯酸（VGB）、加巴喷丁（GBP）和丙戊酸盐（瓦尔）对GAT 1转运蛋白功能的影响。2不仅是众所周知的GAT 1介导的转运抑制剂TGB，而且其它药物也有效地抑制GAT 1对[H-3]-GABA的摄取。VGB、TGB、GBP和瓦尔在浓度分别约为1 nM、1 μ M、50 μ M和100 μ M时，抑制率为50%。3然而，GAT 1介导的稳态和瞬态电流几乎不受VGB、GBP和瓦尔的影响，即使是在高5倍的浓度下。只有TGB在微摩尔浓度下阻断摄取和稳态及瞬态电流。4 VGB与GAT 1表现出复杂的相互作用;在约1 nM浓度下，摄取抑制被释放，但在毫摩尔浓度下，摄取再次被抑制，并且GAT 1介导的电流在这些浓度下最终被K-I值为0.5 mM。摄取抑制的浓度依赖性可以通过具有不同亲和力的两个相互作用位点（阻断位点和转运位点）来解释。5瓦尔、GBP、和VGB对吸收和电流的影响可以归因于GAT 1具有在不吸收GABA的情况下以生电模式运行的能力。我们认为，只有当GAT 1在GABA摄取模式下工作时才会发生抑制。6这四种药物对GABA摄取的抑制将导致突触间隙中GABA浓度的升高，这将增强突触抑制，从而有助于其抗癫痫作用。
1 We have expressed the GABA transporter (GAT1) of mouse brain in Xenopus oocytes and have investigated the effects bf four antiepileptic drugs, tiagabine (TGB), vigabatrin (VGB), gabapentin (GBP) and valproate (VAL), on GAT1 transporter function by measurements of H-3-labelled GABA uptake and GAT1-mediated currents.2 Not only TGB, a well-known inhibitor of GAT1-mediated transport, but also the other drugs efficiently inhibit the uptake of [H-3]-GABA by GAT1. Inhibition at 50% is obtained for VGB, TGB, GBP, and VAL at concentrations of about 1 nM, 1 mu M, 50 mu M and 100 mu M, respectively.3 However, GAT1-mediated steady-state and transient currents are nearly unaffected by VGB, GBP, and VAL at even five times higher concentrations. Only TGB blocks the uptake and steady-state and transient currents at micromolar concentrations.4 VGB exhibits a complex interaction with GAT1; at concentrations about 1 nM, the inhibition of uptake is released, but at millimolar concentrations the uptake is inhibited again, and also the GAT1-mediated current is finally inhibited at these concentrations with a K-I value of 0.5 mM. The concentration dependency of inhibition of uptake can be explained by two interaction sites with different affinities, a blocking site and a transport site.5 The differences in effects of VAL, GBP, and VGB on uptake and currents can be attributed to the fact that GAT1 has the capability to operate in an electrogenic mode without uptake of GABA. We suggest that inhibition occurs only when GAT1 operates in the GABA-uptake mode.6 The inhibition of GABA uptake by these four drugs will result in an elevation of the GABA concentration in the synaptic cleft, which will enhance synaptic inhibition and thereby contribute to their antiepileptic effects.