Investigations into the mechanism of excitant amino acid cytotoxicity using a well-characterized glutamatergic system.
The cytotoxicity of glutamate and several analogues was investigated using a well characterized glutamatergic system; the neuromuscular system of the locust leg. In the presence of Con A (10(-6) M) (which blocks glutamate receptor desensitization) bath application on L-glutamate to isolated nerve-muscle preparations induced degeneration of the muscle cells in a dose-dependent manner. The ability of glutamate analogues to cause similar damage corresponded to their pharmacological potency, i.e. L-quisqualate greater than L-glutamate greater than L-cysteine greater than L-aspartate and L-kainate. Glutamate and the more potent agonists initially caused muscle swelling. This was followed by an increase in opacity of the muscle due to vacuolation resulting from disruption of the sarcoplasmic reticulum. Ca2+-free saline slowed the cytotoxic action of these amino acids, whilst saline containing high concentrations of Ca2+ (20 mM; substituted for Na+) accelerated muscle destruction. Denervation induces supersensitivity of locust muscle to L-glutamate; in denervated muscles the cytotoxicity of L-glutamate was enhanced. Muscles swollen by exposure to high-potassium saline (100 mM; substituted for sodium) were not damaged. We conclude that in this insect glutamatergic system, when desensitization is prevented, activated glutamate receptors gate the influx of Ca2+ and Na2+ causing an ionic imbalance which results in cellular damage. This mechanism could also account for at least some of the neurotoxic effects of amino acids in the vertebrate central nervous system. The results of our studies also indicate that other transmitters which gate non-desensitizing cationic channels should, in principle, also be cytotoxic.
D000818:Animals; D001224:Aspartic Acid / Q000633:toxicity; D003208:Concanavalin A / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005971:Glutamates / Q000633:toxicity*; D018698:Glutamic Acid; D006110:Grasshoppers; D007608:Kainic Acid / Q000633:toxicity; D009410:Nerve Degeneration / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000648:ultrastructure; D018377:Neurotransmitter Agents; D010069:Oxadiazoles / Q000633:toxicity; D016318:Quisqualic Acid; D011956:Receptors, Cell Surface / Q000187:drug effects*; D017470:Receptors, Glutamate; D009435:Synaptic Transmission / Q000187:drug effects*
D005971:Glutamates; D018377:Neurotransmitter Agents; D010069:Oxadiazoles; D011956:Receptors, Cell Surface; D017470:Receptors, Glutamate; D003208:Concanavalin A; D001224:Aspartic Acid; D018698:Glutamic Acid; D016318:Quisqualic Acid; D003545:Cysteine; D007608:Kainic Acid; C013461:cysteine sulfinic acid