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Excitatory Amino Acid‐Mediated Cytotoxicity and Calcium Homeostasis in Cultured Neurons
Author(s) -
Frandsen Aase,
Schousboe Arne
Publication year - 1993
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1993.tb03278.x
Subject(s) - ampa receptor , kainate receptor , calcium , glutamate receptor , chemistry , excitatory postsynaptic potential , calcium in biology , intracellular , neurotoxicity , nmda receptor , biophysics , voltage dependent calcium channel , biochemistry , microbiology and biotechnology , biology , receptor , toxicity , organic chemistry
A large body of evidence suggests that disturbances of Ca 2+ homeostasis may be a causative factor in the neurotoxicity induced by excitatory amino acids (EAAs). The route or routes by which an increase in intracellular calcium concentration ([Ca 2+ ] i ) is mediated in vivo are presently not clarified. This may partly reflect the complexity of intact nervous tissue in combination with the relative unspecific action of the available “calcium antagonists,” e.g., blockers of voltage‐sensitive calcium channels. By using primary cultures of cortical neurons as a model system, it has been found that all EAAs stimulate increases in [Ca 2+ ] i but via different mechanisms. By using the drug dantrolene, it has been shown that 2‐amino‐3‐(3‐hydroxy‐5‐methylisoxazol‐4‐yl)propionate (AMPA) apparently exclusively stimulates Ca 2+ influx through agonist‐operated calcium channels and voltage‐operated calcium channels. Increased [Ca 2+ ] i due to exposure to kainate (KA) is for the major part caused by influx, as in the case of AMPA, but a small part of the increase in [Ca 2+ ] i may be attributed to a release of Ca 2+ from intracellular stores. Quisqualate (QA) stimulates Ca 2+ release from an intracellular store that is independent of Ca 2+ influx; presumably this store is activated by inositol phosphates. The increase in [Ca 2+ ] i due to exposure to glutamate or N ‐methyl‐ d ‐aspartate (NMDA) may be compartmentalized into three components, one of which is related to influx and the other two to Ca 2+ release from internal stores. Only one of the latter stores is dependent on Ca 2+ influx with regard to release of Ca 2+ , whereas the other is activated by some other second messengers or, alternatively, directly coupled to the receptor. In muscles dantrolene is known to inhibit Ca 2+ release from the sarcoplasmic reticulum, and also in neurons dantrolene inhibits an equivalent release from one or more hitherto unidentified internal Ca 2+ pool(s). By using this drug it has been possible to show to what extent these Ca 2+ stores are involved in the toxicity observed subsequent to exposure to the EAAs. It turned out that dantrolene, even under conditions allowing Ca 2+ influx, inhibited toxicity induced by QA, NMDA, and glutamate, whereas that induced by AMPA or KA was unaffected. In combination with the findings that dantrolene inhibited release from the intracellular stores activated by QA, NMDA, and glutamate, it may be concluded that Ca 2+ influx per se is not the primary event causing toxicity following exposure to these EAAs in these neurons. However, it may certainly be involved in the cases of toxicity induced by AMPA and KA. Finally, it should be pointed out that this model only serves as a much simplified working hypothesis and that the situation in vivo is much more complex.