Molecular mechanisms of calcium-dependent excitotoxicity.
Excitotoxicity is thought to be a major mechanism contributing to neurodegeneration during central nervous system ischemia, trauma, and other neurological disorders. Briefly, synaptic overactivity leads to the excessive release of glutamate, the major excitatory neurotransmitter in the mammalian central nervous system. Glutamate activates a number of postsynaptic cell membrane receptors, which upon activation open their associated ion channel pore to produce ion influx or efflux. This leads to a disturbance of the intracellular ionic environment, the best characterized feature of which is the influx of sodium, chloride, and Ca2+. An excess of Ca2+ ions then activates intracellular Ca2+-dependent signaling cascades that eventually lead to neuronal cell death. Despite intensive research in the field of Ca2+-dependent neurotoxicity the precise molecular mechanisms leading to cell death remain poorly understood. In particular, the question of the precise relationship between Ca2+ loading and neurotoxicity has been controversial. Many glutamate receptors are clustered and localized at the postsynaptic density. Recently, increasing knowledge of the molecular composition of the postsynaptic density has allowed us to extend our understanding of the molecular mechanisms of Ca2+-dependent excitotoxicity and to propose that distinct, membrane receptor-specific, neurotoxic signaling pathways transduce Ca2+-dependent excitotoxicity. These findings may have significant implications in the search for precisely targeted therapeutic drugs for a range of neurological disorders.
Sattler
R
R
Toronto Western Hospital Research Institute, Division of Cellular and Molecular Neuroscience, Neuroprotection Laboratory, Ontario, Canada. r_sattler_99@yahoo.com
Tymianski
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D009410:Nerve Degeneration / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology
D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C033652:postsynaptic density proteins; D002118:Calcium