Zeevalk G D, Nicklas W J
University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Department of Neurology, Piscataway 08854, USA.
Vision Res. 1997 Dec;37(24):3463-70. doi: 10.1016/S0042-6989(97)00184-3.
The role of the GABA transporter in acute toxicity in chick retina due to metabolic inhibition was investigated by the use of several substrate (nipecotic acid, THPO) and nonsubstrate (SKF 89976A, NO711) GABA transport inhibitors. Metabolic stress-induced acute toxicity in the retina is characterized by swelling of distinct populations of retinal neurons and selective release of GABA into the medium. Inhibitor concentrations were based on that needed to attenuate 14C-GABA uptake at its approximate KM concentration by > or = 70%. Under basal conditions, substrate, but not nonsubstrate, inhibitors increased extracellular GABA, but did not cause histological swelling per se. Under conditions of glycolytic inhibition, nonsubstrate, but not substrate, inhibitors significantly attenuated acute toxicity. Metabolic stress-induced acute toxicity was not altered by the GABA agonist muscimol, nor did muscimol reverse the protective effects of nonsubstrate transport inhibitors, suggesting that an increase in extracellular GABA during metabolic stress was not a component of the acute phase of toxicity. The results indicate that during metabolic inhibition, activity at the GABA transporter contributes to acute cellular swelling.
通过使用几种底物（哌啶酸、四氢吡咯并[2,3 - b]吡啶）和非底物（SKF 89976A、NO711）GABA转运抑制剂，研究了GABA转运体在代谢抑制导致的雏鸡视网膜急性毒性中的作用。代谢应激诱导的视网膜急性毒性的特征是不同群体的视网膜神经元肿胀以及GABA选择性释放到培养基中。抑制剂浓度基于在其近似KM浓度下使14C - GABA摄取衰减≥70%所需的浓度。在基础条件下，底物抑制剂而非非底物抑制剂增加了细胞外GABA，但本身并未引起组织学肿胀。在糖酵解抑制条件下，非底物抑制剂而非底物抑制剂显著减轻了急性毒性。代谢应激诱导的急性毒性未被GABA激动剂蝇蕈醇改变，蝇蕈醇也未逆转非底物转运抑制剂的保护作用，这表明代谢应激期间细胞外GABA的增加不是毒性急性期的一个组成部分。结果表明，在代谢抑制期间，GABA转运体的活性导致急性细胞肿胀。
