Ethanol modulation of the gamma-aminobutyric acidA- and glycine-activated Cl- current in cultured mouse neurons.
Ethanol modulation of the gamma-aminobutyric acidA- and glycine-activated Cl- current in cultured mouse neurons.
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发表时间：
1994-07
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通讯作者：
L. Aguayo;F. Pancetti
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作者：
L. Aguayo;F. Pancetti
用全细胞技术研究了乙醇对培养的小鼠海马神经元和皮层神经元GABA(γ-氨基丁酸)A激活的氯电流的影响。乙醇(0.25-200 mM)可逆地增强131个海马神经元中68个神经元的电流。乙醇还增强了海马神经元和脊髓神经元士的宁敏感的甘氨酸激活的氯电流。乙醇(40 MM)增强了对GABA的最大反应，但不改变Hill系数(1.2)或受体对GABA的亲和力(EC50=15对14微米)。我们发现神经元对乙醇具有明显的敏感性，甚至425和850 mM的浓度也进一步增强了GABA和甘氨酸诱导的反应。乙醇即使在去除外液中的钙离子后仍能增强GABAA电流。蛋白激酶C激动剂佛波醇、12肉豆蔻酸酯、13醋酸酯对GABA电流幅度的抑制作用为对照组的73%+/-7%，而其非活性类似物4-α佛波醇、12肉豆蔻酸酯、13醋酸酯对此无影响。此外，预先应用1微米佛波醇、12肉豆蔻酸酯、13醋酸酯2分钟可使乙醇增强效应从140+/-8降至122+/-6%。GABA和甘氨酸激活的氯电流的记录表明，低浓度的乙醇可以不同地影响单个神经元中的这两种受体。这表明乙醇的GABA能效应不是由非特异性改变介导的，乙醇对这两种配基激活的氯离子通道的增强机制可能不同。此外，高浓度时没有饱和，这表明乙醇通过作用于几个位置来调节这些受体-离子通道复合体，其中一个可能控制受体磷酸化的状态。
The effects of ethanol on the GABA (gamma-aminobutyric acid)A-activated Cl- current were studied in cultured mouse hippocampal and cortical neurons using whole-cell techniques. Ethanol (0.25-200 mM) reversibly potentiated the current in 68 of the 131 hippocampal neurons examined. Ethanol also potentiated a strychnine-sensitive glycine-activated Cl- current in hippocampal and spinal neurons. Ethanol (40 mM) enhanced the maximal response to GABA without changing the Hill coefficient (1.2) or the affinity of the receptor for GABA (EC50 = 15 vs. 14 microM). We found neurons with distinct sensitivities to ethanol, and even concentrations of 425 and 850 mM further potentiated the response induced by GABA and glycine. Ethanol was able to potentiate the GABAA current even after removing Ca++ from the external solution. The protein kinase C activator phorbol, 12 myristate, 13 acetate inhibited the amplitude of the GABA current by 73 +/- 7% of control; however, 4-alpha-phorbol, 12 myristate, 13 acetate, its inactive analog, had no effects. In addition, 2 min of preapplication of 1 microM phorbol, 12 myristate, 13 acetate reduced the ethanol-potentiation from 140 +/- 8 to 122 +/- 6%. Recordings of GABA- and glycine-activated Cl- currents showed that low concentrations of ethanol can differentially affect these receptors in a single neuron. This suggests that the GABAergic effect of ethanol is not mediated by a nonspecific change and that different mechanisms might account for the potentiation of these two ligand-activated Cl- channels by ethanol. In addition, the absence of saturation with high concentrations suggests that ethanol modulates these receptor-ion channel complexes by acting in several sites, one of which might control the state of receptor phosphorylation.