ACET is a highly potent and specific kainate receptor antagonist: characterisation and effects on hippocampal mossy fibre function.
ACET is a highly potent and specific kainate receptor antagonist: characterisation and effects on hippocampal mossy fibre function.
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DOI：
10.1016/j.neuropharm.2008.08.016
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发表时间：
2009-01
影响因子：
4.7
通讯作者：
Collingridge GL
中科院分区：
文献类型：
--
作者：
Dargan SL;Clarke VR;Alushin GM;Sherwood JL;Nisticò R;Bortolotto ZA;Ogden AM;Bleakman D;Doherty AJ;Lodge D;Mayer ML;Fitzjohn SM;Jane DE;Collingridge GL
红藻氨酸受体（KARs）参与海马CA 3区苔藓纤维突触的NMDA受体非依赖性长时程增强（LTP）和突触易化。然而，涉及的KAR亚型的身份仍然存在争议。在这里，我们使用了一个高度有效的和选择性的GluK 1（以前的GluR 5）拮抗剂（ACET）来阐明这些突触过程中的GluK 1-含有KARs的作用。我们证实ACET是一种非常有效的GluK 1拮抗剂，Kb值为1.4 ± 0.2 nM。相比之下，ACET在所有测试浓度（高达100 μM）下对GluK 2（以前的GluR 6）受体无效，并且在1 μM下测试时对GluK 3（以前的GluR 7）没有影响。与GluK 1配体结合核心结合的ACET的X射线晶体结构与UBP 310-GluK 1复合物相似。在海马脑片CA 1区，ACET可有效阻断GluK 1选择性激动剂ATPA引起的fEPSP和单突触诱发的GABA能传递的抑制。在海马CA 3区，ACET阻断NMDA受体非依赖性苔藓纤维LTP的诱导。直接调查的作用，突触前GluK 1-含有KARs，我们结合膜片钳电生理学和2-光子显微镜图像钙离子动力学在个别巨大的苔藓纤维扣。ACET持续降低由20-25 Hz诱发的5个动作电位诱导的突触前钙瞬变的短期易化。总之，我们的数据提供了进一步的证据，GluK 1-含有KARs在突触促进和LTP诱导苔藓纤维-CA 3突触的生理作用。
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 GluR5) 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 Kb value of 1.4 ± 0.2 nM. In contrast, ACET was ineffective at GluK2 (formerly GluR6) receptors at all concentrations tested (up to 100 μM) and had no effect at GluK3 (formerly GluR7) when tested at 1 μM. 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.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.7
作者：
Blackburn-Munro, G;Bomholt, SF;Erichsen, HK
通讯作者：
Erichsen, HK
影响因子：
25
作者：
Henze, DA;Wittner, L;Buzsáki, G
通讯作者：
Buzsáki, G
影响因子：
3
作者：
Anderson, William W.;Collingridge, Graham L.
通讯作者：
Collingridge, Graham L.
影响因子：
64.8
作者：
Clarke, VRJ;Ballyk, BA;Bleakman, D
通讯作者：
Bleakman, D