Factors Regulating Excitotoxic Neurodegeneration: The Role of Calcium and the Mitochondria
Glutamate is the most widely used excitatory neurotransmitter in the central nervous system. In keeping with its important role in synaptic communication, we know that glutamate-mediated neurotransmission is mediated by a very large number of glutamate receptors (GluRs) which include families of both ionotropic (iGluRs) and metabotropic (mGluRs) receptors. Activation of these receptors can trigger several important phenomena. These include fast synaptic excitation, long-term potentiation, and excitotoxic neuronal degeneration. The molecular basis for these phenomena have been increasingly well understood over the last few years. For example, fast synaptic excitation depends on the influx of Na through activated ionotropic GluRs. On the other hand, longer-term glutamate-mediated events are linked to the influx of Ca through these receptor-gated ion channels (Choi 1988; Meldrum and Garthwaite 1990). Research from a number of laboratories has shown that the Ca permeability of ionotropic GluRs is subject to a number of control mechanisms which include the subunit composition of the receptor, editing of subunit specific mRNA, etc. Although the precise significance of all of these factors is not completely understood at this time, it appears that glutamate-activated Ca influx can potentially be very finely tuned (Burnashev et al. 1992).
KeywordsAmyotrophic Lateral Sclerosis Metabotropic Glutamate Receptor Kainic Acid Mitochondrial Depolarization Hippocampal Pyramidal Neuron
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