Neurotoxicity at the N-methyl-D-aspartate receptor in energy-compromised
neurons. An hypothesis for cell death in aging and disease.
Henneberry RC; Novelli A; Cox JA; Lysko PG
Molecular Neurobiology Section, National Institute of Neurological and
Communicative, Disorders & Stroke, National Institutes of Health, Bethesda,
Ann N Y Acad Sci, 568():225-33 1989
Our results demonstrated that the neurotoxicity of glutamate and closely
related agonists was mediated by the NMDA receptor in rat cerebellar granule
cells. Evidence was presented to support our hypothesis that the pivotal
event in the transition of these EAAs from neurotransmitters to neurotoxins
is relief of the voltage-dependent Mg++ block of the NMDA channel due to
changes in membrane potential which can be caused by depletion of highly
phosphorylated nucleotides or by other depolarizing stimuli. Persistent
stimulation of NMDA receptors whose channels are unblocked by Mg++ can
permit excessive influx of Na+ and Ca++ and neuronal death can follow by a
mechanism not yet understood. Glutamate is not toxic at kainate receptors
although they are present on these cells. These findings underline the
potential importance of perturbations in energy metabolism in a variety of
neurodegenerative disorders and in the normal process of aging which share
the common feature of the loss of neurons.
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