Autere A M, Lamsa K, Kaila K, Taira T
Department of Biosciences, Division of Animal Physiology, University of Helsinki, FIN-00014 Helsinki, Finland.
J Neurophysiol. 1999 Feb;81(2):811-6. doi: 10.1152/jn.1999.81.2.811.
Synaptically evoked transmembrane movements of Ca2+ in the adult CNS have almost exclusively been attributed to activation of glutamate receptor channels and the consequent triggering of voltage-gated calcium channels (VGCCs). Using microelectrodes for measuring free extracellular Ca2+ ([Ca2+]o) and extracellular space (ECS) volume, we show here for the first time that synaptic stimulation of gamma-aminobutyric acid-A (GABAA) receptors can result in a decrease in [Ca2+]o in adult rat hippocampal slices. High-frequency stimulation (100-200 Hz, 0.4-0.5 s) applied in stratum radiatum close (</=0.5 mm) to the recording site induced a 0.1- to 0.3-mM transient fall in [Ca2+]o from a baseline level of 1.6 mM. Concomitantly, a 30-40% decrease in the ECS volume was seen. Exposure of drug-naïve slices to the GABAA receptor antagonist picrotoxin (100 microM) first attenuated and only thereafter augmented the Ca2+ shifts. Application of ionotropic glutamate receptor antagonists resulted in a monotonic reduction of the Ca2+ response, but a large Ca2+ shift persisted (60-70% of the original), which was attenuated by a subsequent application of picrotoxin or bicuculline. In the absence of ionotropic glutamatergic transmission, pentobarbital sodium (100 microM), an up-modulator of the GABAA receptor, strongly enhanced the activity-evoked changes in [Ca2+]o. We suggest that the underlying mechanism of GABA-induced Ca2+ transients is the activation of VGCCs by bicarbonate-dependent GABA-mediated depolarizing postsynaptic potentials. Accordingly, stimulation-evoked Ca2+ shifts were inhibited by the membrane-permeant inhibitor of carbonic anhydrase, ethoxyzolamide (50 microM) or in N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES)-buffered HCO3-free solution. Neuronal Ca2+ uptake caused by intense synaptic activation of GABAA receptors may prove to be an important mechanism in the modulation of activity-dependent neuronal plasticity, epileptogenesis, and cell survival in the adult brain.
在成体中枢神经系统中，由突触诱发的Ca2+跨膜运动几乎完全归因于谷氨酸受体通道的激活以及随之触发的电压门控钙通道（VGCCs）。我们使用微电极测量细胞外游离Ca2+（[Ca2+]o）和细胞外空间（ECS）体积，首次在此表明，γ-氨基丁酸-A（GABAA）受体的突触刺激可导致成年大鼠海马切片中[Ca2+]o降低。在靠近记录位点（≤0.5 mm）的辐射层施加高频刺激（100 - 200 Hz，0.4 - 0.5 s），可使[Ca2+]o从1.6 mM的基线水平短暂下降0.1 - 0.3 mM。同时，观察到ECS体积减少30 - 40%。将未接触过药物的切片暴露于GABAA受体拮抗剂印防己毒素（100 μM），首先会减弱随后才增强Ca2+的变化。应用离子型谷氨酸受体拮抗剂会使Ca2+反应单调降低，但仍会持续出现较大的Ca2+变化（为原始值的60 - 70%），随后应用印防己毒素或荷包牡丹碱可使其减弱。在不存在离子型谷氨酸能传递的情况下，GABAA受体的上调调节剂戊巴比妥钠（100 μM）会强烈增强活动诱发的[Ca2+]o变化。我们认为，GABA诱导的Ca2+瞬变的潜在机制是依赖碳酸氢盐的GABA介导的去极化突触后电位激活VGCCs。因此，刺激诱发的Ca2+变化可被碳酸酐酶的膜通透性抑制剂乙氧唑胺（50 μM）或在N - 2 - 羟乙基哌嗪 - N' - 2 - 乙磺酸（HEPES）缓冲的无HCO3溶液中抑制。GABAA受体强烈的突触激活所引起的神经元Ca2+摄取可能是调节成体大脑中活动依赖性神经元可塑性、癫痫发生和细胞存活的重要机制。
