Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity.
Excitotoxicity contributes to neuronal degeneration in many acute CNS diseases, including ischemia, trauma, and epilepsy, and may also play a role in chronic diseases, such as amyotrophic lateral sclerosis (ALS). Key mediators of excitotoxic damage are Ca ions (Ca(2+)), which under physiological conditions govern a multitude of cellular processes, including cell growth, differentiation, and synaptic activity. Consequently, homeostatic mechanisms exist to maintain a low intracellular Ca(2+) ion concentration so that Ca(2+) signals remain spatially and temporally localized. This permits multiple independent Ca-mediated signaling pathways to occur in the same cell. In excitotoxicity, excessive synaptic release of glutamate can lead to the disregulation of Ca(2+) homeostasis. Glutamate activates postsynaptic receptors, including the ionotropic N-methyl-D-aspartate (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) proprionate (AMPA), and kainate receptors. Upon their activation, these open their associated ion channel to allow the influx of Ca(2+) and Na(+) ions. Although physiological elevations in intracellular Ca(2+) are salient to normal cell functioning, the excessive influx of Ca(2+) together with any Ca(2+) release from intracellular compartments can overwhelm Ca(2+)-regulatory mechanisms and lead to cell death. Although Ca(2+) disregulation is paramount to neurodegeneration, the exact mechanism by which Ca(2+) ions actually mediate excitotoxicity is less clear. One hypothesis outlined in this review suggests that Ca(2+)-dependent neurotoxicity occurs following the activation of distinct signaling cascades downstream from key points of Ca(2+) entry at synapses, and that triggers of these cascades are physically co-localized with specific glutamate receptors. Thus, we summarize the importance of Ca(2+) regulation in mammalian neurons and the excitotoxicity hypothesis, and focus on the molecular determinants of glutamate receptor-mediated excitotoxic mechanisms.
Arundine
Mark
M
Toronto Western Hospital Research Institute, 399 Bathurst Street, Ont. M5T 2S8, Toronto, Canada.
Tymianski
Michael
M
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000633:toxicity; D020013:Calcium Signaling / Q000502:physiology; D018698:Glutamic Acid / Q000502:physiology; D051528:Guanylate Kinases; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000503:physiopathology; D009498:Neurotoxins / Q000378:metabolism*; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism; D018091:Receptors, AMPA / Q000737:chemistry / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000502:physiology
D008565:Membrane Proteins; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D018698:Glutamic Acid; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases; D002118:Calcium