Glutamate triggers preferential Zn2+ flux through Ca2+ permeable AMPA channels and consequent ROS production.
ZN2+ co-released with glutamate at excitatory synaptic sites can enter and cause injury to postsynaptic neurons. While prior studies using the slowly desensitizing agonist kainate suggested preferential Zn2+ permeation through Ca2+ permeable AMPA/kainate (Ca-A/K) channels, the present study aims to assess relevance of those findings upon more physiological receptor activation. Microfluorimetric techniques were used to measure [Zn2+]i attained upon exposure to the rapidly desensitizing agonist AMPA or to the physiological agonist glutamate, in the presence of 300 microM Zn2+. Under these conditions, micromolar [Zn2+]i rises (delta[Zn2+]i) were still observed to occur selectively in the subset of neurons that express large numbers of Ca-A/ K channels. Further studies using the oxidation sensitive dye, hydroethidine, revealed Zn2+-dependent reactive oxygen species generation that paralleled delta[Zn2+]i, with rapid oxidation only observed in the case of Zn2+ entry through Ca-A/K channels.
Sensi
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SL
Department of Neurology, University of California, Irvine 92697-4292, USA.
Yin
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HZ
Weiss
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JH
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005456:Fluorescent Dyes; D005470:Fluorometry; D018698:Glutamic Acid / Q000494:pharmacology / Q000502:physiology*; D007091:Image Processing, Computer-Assisted; D066298:In Vitro Techniques; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010617:Phenanthridines; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D015220:Calcium Channels; D018690:Excitatory Amino Acid Agonists; D005456:Fluorescent Dyes; D010617:Phenanthridines; D017382:Reactive Oxygen Species; D018091:Receptors, AMPA; C058428:hydroethidine; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D015032:Zinc