AMPA receptor activation potentiates zinc neurotoxicity.
Extracellular Zn2+ attenuates NMDA receptor-mediated neurotoxicity and increases AMPA receptor-mediated toxicity. Known electrophysiological effects of Zn2+ predict only the former. We considered the possibility that the latter rather reflects AMPA potentiation of Zn2+ toxicity, perhaps mediated by neuronal depolarization and Zn2+ entry through voltage-gated Ca2+ channels. High K+ or kainate also potentiated Zn2+ toxicity, and AMPA plus Zn2+ toxicity was attenuated by raising extracellular Ca2+, or by Ca2+ channel blockers. AMPA plus Zn2+ exposure induced an increase in fluorescence from neurons loaded with the Zn(2+)-sensitive dye TS-Q and increased subsequent 45Ca2+ accumulation. The ability of AMPA receptor activation to potentiate Zn2+ toxicity may be relevant to neuronal death associated with intense activation of glutamatergic pathways.
Weiss
J H
JH
Department of Neurolog, University of California Irvine 92717.
Hartley
D M
DM
Koh
J Y
JY
Choi
D W
DW
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D002478:Cells, Cultured; D004357:Drug Synergism; D007051:Ibotenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D009422:Nervous System Diseases / Q000139:chemically induced*; D011188:Potassium / Q000494:pharmacology; D018091:Receptors, AMPA; D017470:Receptors, Glutamate / Q000187:drug effects / Q000502:physiology*; D015032:Zinc / Q000494:pharmacology / Q000633:toxicity*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D015220:Calcium Channels; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D007051:Ibotenic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D015032:Zinc; D011188:Potassium; D007608:Kainic Acid; D002118:Calcium