Vignes M, Clarke V R, Parry M J, Bleakman D, Lodge D, Ornstein P L, Collingridge G L
Department of Anatomy, University of Bristol, UK.
Neuropharmacology. 1998 Oct-Nov;37(10-11):1269-77. doi: 10.1016/s0028-3908(98)00148-8.
Activation of kainate receptors depresses excitatory synaptic transmission in the hippocampus. In the present study, we have utilised a GluR5 selective agonist, ATPA [(RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid], and a GluR5 selective antagonist, LY294486 [(3SR,4aRS,6SR,8aRS)-6-([[(1H-tetrazol-5-y l)methyl]oxy]methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3 -carboxylic acid], to determine whether GluR5 subunits are involved in this effect. ATPA mimicked the presynaptic depressant effects of kainate in the CA1 region of the hippocampus. It depressed reversibly AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor-mediated field excitatory postsynaptic potentials (field EPSPs) with an IC50 value of approximately 0.60 microM. The dual-component excitatory postsynaptic current (EPSC) and the pharmacologically isolated NMDA (N-methyl-D-aspartate) receptor-mediated EPSC were depressed to a similar extent by 2 microM ATPA (61 +/- 7% and 58 +/- 6%, respectively). Depressions were associated with an increase in the paired-pulse facilitation ratio suggesting a presynaptic locus of action. LY294486 (20 microM) blocked the effects of 2 microM ATPA on NMDA receptor-mediated EPSCs in a reversible manner. In area CA3, 1 microM ATPA depressed reversibly mossy fibre-evoked synaptic transmission (by 82 +/- 10%). The effects of ATPA were not accompanied by any changes in the passive properties of CA1 or CA3 neurones. However, in experiments where K+, rather than Cs+, containing electrodes were used, a small outward current was observed. These results show that GluR5 subunits comprise or contribute to a kainate receptor that regulates excitatory synaptic transmission in both the CA1 and CA3 regions of the hippocampus.
海人酸受体的激活会抑制海马体中的兴奋性突触传递。在本研究中，我们使用了一种GluR5选择性激动剂ATPA [（RS）-2-氨基-3-（3-羟基-5-叔丁基异恶唑-4-基）丙酸]和一种GluR5选择性拮抗剂LY294486 [（3SR，4aRS，6SR，8aRS）-6-（[[（1H-四唑-5-基）甲基]氧基]甲基）-1,2,3,4,4a,5,6,7,8,8a-十氢异喹啉-3-羧酸]，以确定GluR5亚基是否参与了这一效应。ATPA模拟了海人酸在海马体CA1区的突触前抑制作用。它可逆地抑制AMPA（α-氨基-3-羟基-5-甲基异恶唑-4-丙酸）受体介导的场兴奋性突触后电位（场EPSP），IC50值约为0.60微摩尔。2微摩尔的ATPA使双成分兴奋性突触后电流（EPSC）和药理学分离的NMDA（N-甲基-D-天冬氨酸）受体介导的EPSC受到类似程度的抑制（分别为61±7%和58±6%）。抑制与成对脉冲易化率的增加相关，提示作用位点在突触前。LY294486（20微摩尔）以可逆的方式阻断了2微摩尔ATPA对NMDA受体介导的EPSC的作用。在CA3区，1微摩尔的ATPA可逆地抑制苔藓纤维诱发的突触传递（抑制82±10%）。ATPA的作用并未伴随CA1或CA3神经元被动特性的任何变化。然而，在使用含钾而非铯电极的实验中，观察到了一个小的外向电流。这些结果表明，GluR5亚基构成或促成了一种海人酸受体，该受体调节海马体CA1和CA3区的兴奋性突触传递。
