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.
McDonald
J W
JW
Center for the Study of Nervous System Injury and Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Bhattacharyya
T
T
Sensi
S L
SL
Lobner
D
D
Ying
H S
HS
Canzoniero
L M
LM
Choi
D W
DW
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