NMDA-receptor mediated efflux of N-acetylaspartate: physiological and/or pathological importance?
N-Acetylaspartate (NAA) is a largely neuron specific dianionic amino acid present in high concentration in vertebrate brain. Many fundamental questions concerning N-acetylaspartate in brain remain unanswered. One such issue is the predominantly neuronal synthesis and largely glial catabolism which implies the existence of a regulated efflux from neurons. Here we show that transient (5 min) NMDA-receptor activation (60 microM) induces a long lasting Ca2+ -dependent efflux of N-acetylaspartate from organotypic slices of rat hippocampus. The NMDA-receptor stimulated efflux was unaffected by hyper-osmotic conditions (120 mM sucrose) and no efflux of N-acetylaspartate was evoked by high K+ -depolarization (50 mM) or kainate (300 microM). These results indicate that the efflux induced by NMDA is not related directly to either cell swelling or depolarization but is coupled to Ca2+ -influx via the NMDA-receptor. The efflux of N-acetylaspartate persisted at least 20 min after the omission of NMDA, similar to the efflux of the organic anions glutathione and phosphoethanolamine. The efflux of taurine and hypotaurine was also stimulated by NMDA but returned more quickly to basal levels. The NMDA-receptor stimulated efflux of N-acetylaspartate, glutathione, phosphoethanolamine, taurine and hypotaurine correlated with delayed nerve cell death measured 24 h after the transient NMDA-receptor stimulation. However, exogenous administration of high concentrations of N-acetylaspartate to the culture medium was non-toxic. The results suggest that Ca2+ -influx via the NMDA-receptor regulates the efflux of N-acetylaspartate from neurons which may have both physiological and pathological importance.
Tranberg
Mattias
M
Department of Medical Biophysics, Göteborg University, Göteborg, Sweden.
Stridh
Malin H
MH
Guy
Yifat
Y
Jilderos
Barbro
B
Wigström
Holger
H
Weber
Stephen G
SG
Sandberg
Mats
M
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism*; D016923:Cell Death; D002851:Chromatography, High Pressure Liquid; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009924:Organ Culture Techniques; D011188:Potassium / Q000378:metabolism; D011419:Propidium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013056:Spectrophotometry, Ultraviolet
D000596:Amino Acids; D018690:Excitatory Amino Acid Agonists; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D001224:Aspartic Acid; D011419:Propidium; D016202:N-Methylaspartate; C000179:N-acetylaspartate; D005978:Glutathione; D011188:Potassium; D007608:Kainic Acid