ACET is a highly potent and specific kainate receptor antagonist: Characterisation and effects on hippocampal mossy fibre function

NEUROPHARMACOLOGY

卷:56

Article

Dargan, Sheila L.¹  Clarke, Vernon R. J.¹  Alushin, Gregory M.²  Sherwood, John L.¹  Nistico, Robert¹  Bortolotto, Zuner A.¹  Ogden, Ann M.³  Bleakman, David³  Doherty, Andrew J.¹  Lodge, David¹  Mayer, Mark L.²  Fitzjohn, Stephen M.¹  Jane, David E.¹  Collingridge, Graham L.¹ 

[1] Univ Bristol, MRC Ctr Synapt Plast, Bristol BS8 1TD, Avon, England

[2] NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA

[3] Eli Lilly & Co, Lilly Corp Ctr, Neurosci Res, Indianapolis, IN 46285 USA

关键词: Hippocampus;    Mossy fibre LTP;    Calcium;    Kainate;    ACET;    GluR5;    GluK1;    X-ray crystallography;    2-Photon;   

DOI  :  10.1016/j.neuropharm.2008.08.016

来源: Elsevier

【 摘 要 】

Kainate receptors (KARs) are involved in both NMDA receptor-independent long-term potentiation (LTP) and synaptic facilitation at mossy fibre synapses in the CA3 region of the hippocampus. However, the identity of the KAR subtypes involved remains controversial. Here we used a highly potent and selective GluK1 (formerly G1uR5) antagonist (ACET) to elucidate roles of GluK1-containing KARs in these synaptic processes. We confirmed that ACET is an extremely potent GluK1 antagonist, with a K-b value of 1.4 +/- 0.2 nM. In contrast, ACET was ineffective at GluK2 (formerly GluR6) receptors at all concentrations tested (up to 100 mu M) and had no effect at GluK3 (formerly GluR7) when tested at 1 mu M. The X-ray crystal structure of ACET bound to the ligand binding core of GluK1 was similar to the UBP310-GluK1 complex. In the CA1 region of hippocampal slices, ACET was effective at blocking the depression of both fEPSPs and monosynaptically evoked GABAergic transmission induced by ATPA, a GluK1 selective agonist. In the CA3 region of the hippocampus, ACET blocked the induction of NMDA receptor-independent mossy fibre LTP. To directly investigate the role of pre-synaptic GluK1-containing KARs we combined patch-clamp electrophysiology and 2-photon microscopy to image Ca2+ dynamics in individual giant mossy fibre boutons. ACET consistently reduced short-term facilitation of pre-synaptic calcium transients induced by 5 action potentials evoked at 20-25 Hz. Taken together our data provide further evidence for a physiological role of GluK1-containing KARs in synaptic facilitation and LTP induction at mossy fibre-CA3 synapses. (C) 2008 Elsevier Ltd. All rights reserved.

【 授权许可】

Free