Modulation of Tonic GABA Currents by Anion Channel and Connexin Hemichannel Antagonists.
Modulation of Tonic GABA Currents by Anion Channel and Connexin Hemichannel Antagonists.
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DOI：
10.1007/s11064-017-2246-4
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发表时间：
2017-09
影响因子：
4.4
通讯作者：
Richerson, George B.
中科院分区：
文献类型：
--
作者：
Ransom, Christopher B.;Ye, Zucheng;Spain, William J.;Richerson, George B.
阴离子通道和连接蛋白半通道可渗透氨基酸神经递质。假设这些传导途径释放GABA，从而影响环境中GABA水平和强直性GABA能抑制。为此，我们测量了阴离子通道/半通道拮抗剂对大鼠海马神经元强直性GABA电流的影响。与预测相反，NPPB阻断阴离子通道和半通道增强了培养和急性海马切片神经元的强直性GABA电流。相反，阴离子通道/半通道拮抗剂卡贝诺洛酮（CBX）抑制强直电流。这些结果可能是由于环境GABA浓度的改变或对GABAA受体的直接影响。为了测试对GABAA受体的影响，我们测量了外源GABA引起的电流。NPPB与GABA共应用可增强GABA诱发电流。CBX剂量依赖性地抑制gaba诱发电流。这些结果与NPPB和CBX对GABAA受体的直接作用一致。用高效液相色谱法直接测定海马细胞培养物中GABA的释放量。用NPPB或CBX抑制阴离子通道不影响培养海马神经元GABA的释放。NPPB使纯星形胶质细胞释放的GABA减少21%，但与混合培养相比，星形胶质细胞释放的GABA总量较少。这些数据表明，通常用于拮抗阴离子通道和连接蛋白半通道的药物可能通过直接作用于GABAA受体来影响紧张电流，而对环境GABA浓度的影响可以忽略不计。解释使用NPPB或CBX的实验应包括考虑它们对强直性GABA电流的影响。
Anion channels and connexin hemichannels are permeable to amino acid neurotransmitters. It is hypothesized that these conductive pathways release GABA, thereby influencing ambient GABA levels and tonic GABAergic inhibition. To investigate this, we measured the effects of anion channel/hemichannel antagonists on tonic GABA currents of rat hippocampal neurons. In contrast to predictions, blockade of anion channels and hemichannels with NPPB potentiated tonic GABA currents of neurons in culture and acute hippocampal slices. In contrast, the anion channel/hemichannel antagonist carbenoxolone (CBX) inhibited tonic currents. These findings could result from alterations of ambient GABA concentration or direct effects on GABAA receptors. To test for effects on GABAA receptors, we measured currents evoked by exogenous GABA. Coapplication of NPPB with GABA potentiated GABA-evoked currents. CBX dose-dependently inhibited GABA-evoked currents. These results are consistent with direct effects of NPPB and CBX on GABAA receptors. GABA release from hippocampal cell cultures was directly measured using HPLC. Inhibition of anion channels with NPPB or CBX did not affect GABA release from cultured hippocampal neurons. NPPB reduced GABA release from pure astrocytic cultures by 21%, but the total GABA release from astrocytes was small compared to that of mixed cultures. These data indicate that drugs commonly used to antagonize anion channels and connexin hemichannels may affect tonic currents via direct effects on GABAA receptors and have negligible effects on ambient GABA concentrations. Interpretation of experiments using NPPB or CBX should include consideration of their effects on tonic GABA currents.
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影响因子：
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通讯作者：
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