Extracellular acidity potentiates AMPA receptor-mediated cortical neuronal death.
The extracellular acidity that accompanies brain hypoxia-ischemia is known to reduce both NMDA and AMPA-kainate receptor-mediated currents and NMDA receptor-mediated neurotoxicity. Although a protective effect of acidic pH on AMPA-kainate receptor-mediated excitotoxicity has been assumed, such has not been demonstrated. Paradoxically, we found that lowering extracellular pH selectively increased AMPA-kainate receptor-mediated neurotoxicity in neocortical cell cultures, despite reducing peak elevations in intracellular free Ca2+. This injury potentiation may, at least in part, be related to a slowed recovery of intracellular Ca2+ homeostasis, observed after AMPA-kainate receptor activation, but not after NMDA receptor activation or exposure to high K+. The ability of acidic pH to selectively augment AMPA-kainate receptor-mediated excitotoxicity may contribute to the prominent role that these receptors play in selective neuronal death after transient global ischemia.
Center for the Study of Nervous System Injury and Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J W
JW
McDonald
T
T
Bhattacharyya
S L
SL
Sensi
D
D
Lobner
H S
HS
Ying
L M
LM
Canzoniero
D W
DW
Choi
D000143:Acids / Q000378:metabolism*; D000693:Anaerobiosis / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice / Q000196:embryology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D018091:Receptors, AMPA / Q000502:physiology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D000143:Acids; D018690:Excitatory Amino Acid Agonists; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D005947:Glucose; D007608:Kainic Acid; D002118:Calcium