Clarke V R, Ballyk B A, Hoo K H, Mandelzys A, Pellizzari A, Bath C P, Thomas J, Sharpe E F, Davies C H, Ornstein P L, Schoepp D D, Kamboj R K, Collingridge G L, Lodge D, Bleakman D
Department of Anatomy, University of Bristol, UK.
Nature. 1997 Oct 9;389(6651):599-603. doi: 10.1038/39315.
The principal excitatory neurotransmitter in the vertebrate central nervous system, L-glutamate, acts on three classes of ionotripic glutamate receptors, named after the agonists AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxalole-4-propionic acid), NMDA (N-methyl-D-aspartate) and kainate. The development of selective pharmacological agents has led to a detailed understanding of the physiological and pathological roles of AMPA and NMDA receptors. In contrast, the lack of selective kainate receptor ligands has greatly hindered progress in understanding the roles of kainate receptors. Here we describe the effects of a potent and selective agonist, ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid) and a selective antagonist, LY294486 ((3SR, 4aRS, 6SR, 8aRS)-6-((((1H-tetrazol-5-yl) methyl)oxy)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylic acid), of the GluR5 subtype of kainate receptor. We have used these agents to show that kainate receptors, comprised of or containing GluR5 subunits, regulate synaptic inhibition in the hippocampus, an action that could contribute to the epileptogenic effects of kainate.
L-谷氨酸是脊椎动物中枢神经系统中的主要兴奋性神经递质，作用于三类离子型谷氨酸受体，它们以激动剂AMPA（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸）、NMDA（N-甲基-D-天冬氨酸）和海人藻酸命名。选择性药理剂的开发使人们对AMPA和NMDA受体的生理和病理作用有了详细了解。相比之下，缺乏选择性海人藻酸受体配体极大地阻碍了对海人藻酸受体作用的理解。本文描述了一种强效选择性激动剂ATPA（(RS)-2-氨基-3-(3-羟基-5-叔丁基异恶唑-4-基)丙酸）和一种选择性拮抗剂LY294486（(3SR, 4aRS, 6SR, 8aRS)-6-((((1H-四氮唑-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）对海人藻酸受体GluR5亚型的作用。我们使用这些药剂证明，由GluR5亚基组成或包含GluR5亚基的海人藻酸受体调节海马体中的突触抑制，这一作用可能导致海人藻酸的致癫痫作用。
