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Concentration-dependent substrate behavior of native AMPA receptors

NATURE NEUROSCIENCE 2000年第10期3卷 992-997页

作者： Smith, TC Howe, JR Yale Univ Sch Med Dept Pharmacol New Haven CT 06520 USA

AMPA-type glutamate receptors mediate most excitatory postsynaptic currents (EPSCs) at central synapses, and their conductance determines in part the size of EPSCs. The conductance of a recombinant AMPA receptor depends on the number of agonist molecules bound to the channel. Here we tested whether native AMPA and kainate receptors show this behavior in outside-out patches from neurons in situ by measuring conductance levels of single channels over a wide range of agonist concentrations. We found that the conductance of AMPA, but not kainate, receptors depended strongly on agonist concentration. Our results suggest that alterations in the glutamate concentration in the synaptic cleft may change the apparent unitary conductance of postsynaptic AMPA receptors.

关键词：动物新生剂量效应关系药物兴奋性氨基酸拮抗剂/药理学兴奋性突触后电位/药物作用兴奋性突触后电位/生理学谷氨酸/代谢谷氨酸/药理学离子通道/药物作用离子通道/代谢红藻氨酸/类似物和衍生物红藻氨酸/药理学小鼠近交C57BL 神经肌肉去极化药/药理学器官培养技术喹恶啉类/药理学受体 AMPA/激动剂受体 AMPA/药物作用受体 AMPA/代谢受体红藻氨酸/激动剂受体红藻氨酸/药物作用受体红藻氨酸/代谢突触膜/药物作用突触膜/代谢动物小鼠

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AMPA and kainate receptors each mediate excitotoxicity in oligodendroglial cultures

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NEUROBIOLOGY OF DISEASE 1999年第6期6卷 475-485页

作者： Sánchez-Gómez, MV Matute, C Univ Basque Country Dept Neurociencias Leioa 48940 Vizcaya Spain

Recent studies indicate that oligodendrocytes are vulnerable to excitotoxic insults mediated by glutamate receptors. The present study was carried out to characterize the type of glutamate receptors triggering cell death in optic nerve oligodendrocyte cultures. Acute activation of either AM PA or kainate receptors was toxic to oligodendrocytes, an effect that was prevented by CNQX. However, exposure to agonists of the NMDA and metabotropic glutamate receptors did not impair cell viability. Dose-response curves showed that toxicity was mediated by three distinct populations of receptors: an AMPA-type receptor and high- and low-affinity kainate-type receptors. Expression and immunocytochemical studies suggested that the glutamate receptor subunits give rise to the native receptors in each population. In all instances, Ca2+ entry was a major determinant of glutamate receptor excitotoxicity. However, its influence varied for each receptor subtype. These results indicate that aberrantly enhanced activation of AMPA and/or kainate receptors may be involved in demyelinating diseases. (C) 1999 Academic Press.

关键词：动物新生细胞凋亡/药物作用细胞凋亡/生理学钙/代谢细胞培养的/药物作用细胞培养的/代谢兴奋性氨基酸激动剂/药理学兴奋性氨基酸拮抗剂/药理学谷氨酸/药理学神经毒素类/药理学少突神经胶质/细胞学少突神经胶质/药物作用少突神经胶质/代谢视神经/细胞学视神经/药物作用视神经/代谢大鼠 Sprague-Dawley 受体 AMPA/药物作用受体 AMPA/代谢受体红藻氨酸/药物作用受体红藻氨酸/代谢钠/代谢动物大鼠

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Overexpression of GluR6 in rat hippocampus produces seizures and spontaneous nonsynaptic bursting in vitro

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NEUROBIOLOGY OF DISEASE 2000年第4期7卷 362-374页

作者： Telfeian, AE Federoff, HJ Leone, P During, MJ Williamson, A Yale Univ Sch Med Dept Neurosurg New Haven CT 06520 USA

We hypothesized that overexpression of specific glutamate receptors within the hippocampus would induce seizures and the associated cellular changes seen in temporal lobe epilepsy (TLE). The GluR6 kainate receptor was overexpressed by injecting rat hippocampi with HSVGluR6, a viral vector transducing fully edited GluR6, These animals experienced limbic seizures approximately 4 h following the injection, Control animals injected with HSVlac, a vector expressing beta-galactosidase, did not have seizures. Recordings from hippocampal CA1 pyramidal cells were performed 12 to 48 h and 1 week to 1 month postinjection. We observed nonsynaptic Na C-mediated bursting in 77.5% of cells 12 to 48 h following injection of HSVGluR6 but not HSVlac, The synaptic responses were normal in both groups. However, the physiological properties of cells from HSVGluR6-injected hippocampi changed over time. Two weeks following HSVGluR6 injection, synaptic bursts could be evoked, but intrinsic bursting became rare. These changes persisted for at least 1 month. We postulate that this transition from intrinsic to synaptic hyperexcitability may be important in the development of TLE. (C) 2000 Academic Press.

关键词：动作电位/药物作用动作电位/生理学癫痫颞叶/病因学癫痫颞叶/代谢兴奋性氨基酸拮抗剂/药理学遗传载体/药理学疱疹病毒1型人海马/药物作用海马/代谢神经元/药物作用神经元/代谢受体红藻氨酸/药物作用受体红藻氨酸/代谢发作/病因学发作/代谢钠通道/药物作用钠通道/代谢转染动物大鼠

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Acute effects of ethanol on kainate receptors with different subunit compositions

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期288卷 1199-1206页

作者： Valenzuela, CF Cardoso, RA Univ New Mexico Hlth Sci Ctr Dept Neurosci Albuquerque NM 87131 USA Univ Colorado Hlth Sci Ctr Dept Pharmacol Denver CO 80262 USA

Previous studies showed that recombinant homomeric GluR6 receptors are acutely inhibited by ethanol. This study examined the acute actions of ethanol on recombinant homomeric and heteromeric kainate (KA) receptors with different subunit configurations. Application of 25 to 100 mM ethanol produced inhibition of a similar magnitude of both GluR5-Q and GluR6-R KA receptor-dependent currents in Xenopus oocytes. Ethanol decreased the KA E-max without affecting the EC,, and its effect was independent of the membrane holding potential for both of these receptors subtypes. Ethanol also inhibited homomeric and heteromeric receptors transiently expressed in human embryonic kidney (HEK) 293 cells. In these cells, the expression of heteromeric GluR6-R subunit-containing receptors was confirmed by testing their sensitivity to 1 mM alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. Ethanol inhibited to a similar extent KA-gated currents mediated by receptors composed of either GluR6 or GluR6 + KA1 subunits, and to a slightly lesser extent receptors composed of GluR6 + KA2 subunits. Acute ethanol's effects were tested on GluR5 KA receptors that are expressed as homomers (GluR5-Q) or heteromers (GluR5-R + KA1 and GluR5-R + KA2). Homomeric and heteromeric GluR5 KA receptors were all inhibited to a similar extent by ethanol;however, there was slightly more inhibition of GluR5-R + KA2 receptors. Thus, recombinant KA receptors with different subunit compositions are all acutely inhibited to a similar extent by ethanol. In light of recent reports that KA receptors regulate neurotransmitter release and mediate synaptic currents, we postulate that these receptors may play a role in acute ethanol intoxication.

关键词：细胞系/代谢中枢神经系统抑制药/药理学乙醇/药理学基因表达卵母细胞/代谢膜片钳术受体红藻氨酸/生物合成受体红藻氨酸/药物作用受体红藻氨酸/遗传学重组蛋白质类/药物作用转染爪蟾属动物人类

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Learning about kainate receptors

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TRENDS IN PHARMACOLOGICAL SCIENCES 2000年第5期21卷 159-160页

作者： Reid, CA Bliss, TVP Natl Inst Med Res Div Neurophysiol London NW7 1AA England

Three classes of ionotropic glutamate receptors have been identified: NMDA (N-methyl-d-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid) and kainate (KA) receptors 1. The roles of AMPA and NMDA receptors in mediating fast synaptic transmission and synaptic plasticity, respectively, are well understood; however, the physiological function of the KA receptor family (comprising GluR5–7 and KA1–2 subunits) has remained obscure. This situation has stemmed primarily from the lack of selective pharmacological reagents. A consortium of academic and pharmaceutical laboratories, led by Graham Collingridge's group at the University of Bristol (Bristol, UK) and a group at Eli Lilly in Indianapolis (IN, USA) headed by David Lodge and David Bleakman, has now provided the first evidence for a selective KA receptor antagonist 2. Both in expression systems and at native receptors, the compound LY382884 exhibits potent selective antagonism at KA receptors that contain the GluR5 subunit. Bortolotto et al. have used this powerful new pharmacological tool to explore the role of KA receptors in synaptic plasticity in the mossy fibre projection of the hippocampal formation.

关键词：苔藓纤维海马/代谢受体红藻氨酸/化学受体红藻氨酸/药物作用受体红藻氨酸/代谢动物人类

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The synthesis of 4-arylsulfanyl-substituted kainoid analogues from trans-4-hydroxy-L-proline

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第17期10卷 1927-1929页

作者： Baldwin, JE Pritchard, GJ Williamson, DS Univ Oxford Dyson Perrins Lab Oxford OX1 3QY England

The potent neuroexcitatory activity of kainoid amino acids in the mammalian CNS places new analogues in high demand as tools ibr neuropharmacological research. A range of 4-arylsulfanyl-substituted kainoids has been synthesised in a parallel Fashion via mesylate displacement by a number of aromatic and heteroaromatic thiolates upon (2S,3S,4R)-1-benzoyl-3-tert-butoxycarboxylmethy-4-methanesulfonyloxy pyrrolidine-2-carboxylic acid methyl ester 8, which is obtainable in eight steps from trans-4-hydroxy-L-proline 5. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：羟脯氨酸红藻氨酸/化学合成受体红藻氨酸/药物作用

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