Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced.
The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor appears to play a pivotal role in enabling glutamate to express its neurotoxic potential in a variety of neurological disorders. Our results show that the transition of glutamate from neurotransmitter to neurotoxin is facilitated when cellular energy is limited in cultured cerebellar neurons. Omission of glucose, exclusion of oxygen, or inclusion of inhibitors of oxidative phosphorylation or of the sodium/potassium pump, enables the excitatory amino acids glutamate or NMDA to express their neurotoxic potential. We interpret these results as demonstrating that glucose metabolism, ATP production, and functioning Na+,K+-ATPases are necessary to generate a resting potential sufficient to maintain the voltage-dependent Mg2+ block of the NMDA receptor channel; relief of the Mg2+ block enables the excitatory amino acids to act persistently at the NMDA receptor, resulting in the opening of ion channels and subsequent neuronal damage. These findings are discussed in the context of perturbations or abnormalities which lead to decreased availability or utilization of glucose and oxygen in the brain which may trigger endogenous excitatory amino acids to become neurotoxic by this mechanism.
Novelli
A
A
Laboratory of Molecular Biology, National Institute of Neurological and Communicative Disorders and Stroke, Bethesda, MD 20892.
Reilly
J A
JA
Lysko
P G
PG
Henneberry
R C
RC
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002531:Cerebellum / Q000187:drug effects; D004734:Energy Metabolism; D005971:Glutamates / Q000009:adverse effects* / Q000378:metabolism; D018698:Glutamic Acid; D007473:Ion Channels; D008274:Magnesium / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*
D000596:Amino Acids; D005971:Glutamates; D007473:Ion Channels; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D018698:Glutamic Acid; D008274:Magnesium