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A hippocampal GluR5 kainate receptor regulating inhibitory synaptic transmission

Abstract

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 (α-amino-3-hydroxy-5-methyl-4-isoxalole-4-propionic acid), NMDA ( N -methyl-D-aspartate) and kainate1. The development of selective pharmacological agents has led to a detailed understanding ofthe physiological and pathological roles of AMPA and NMDA receptors2,3,4,5,6,7,8. In contrast, the lack of selective kainate receptor ligands has greatly hindered progress in understanding the rolesof kainate receptors9,10. 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 receptor11. 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 kainate12,13,14,15,16,17.

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Figure 1: a, Structures of ATPA and LY294486.
Figure 2: a, Agonist concentration–response curves of ATPA (circles) and kainate (squares) at human GluR5 receptors expressed in HEK293.
Figure 3: Antagonism of cloned human AMPA and kainate receptors by LY294486.
Figure 4: Activation of GluR5 depresses inhibitory synaptic transmission.

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Acknowledgements

We thank M. Deverill for technical assistance. This work was supported by the MRC (G.L.C.) and the Wellcome Trust (V.R.J.C.).

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Clarke, V., Ballyk, B., Hoo, K. et al. A hippocampal GluR5 kainate receptor regulating inhibitory synaptic transmission. Nature 389, 599–603 (1997). https://doi.org/10.1038/39315

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