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 (Ca2+), 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 Ca2+ ion concentration so that Ca2+ 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 Ca2+ homeostasis. Glutamate activates post-synaptic 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 Ca2+ and Na+ ions. Although physiological elevations in intracellular Ca2+ are salient to normal cell functioning, the excessive influx of Ca2+ together with any Ca2+ release from intracellular compartments can overwhelm Ca2+-regulatory mechanisms and lead to cell death. Although Ca2+ disregulation is paramount to neurodegeneration, the exact mechanism by which Ca2+ ions actually mediate excitotoxicity is less clear. One hypothesis outlined in this review suggests that Ca2+-dependent neurotoxicity occurs following the activation of distinct signaling cascades downstream from key points of Ca2+ entry at synapses, and that triggers of these cascades are physically co-localized with specific glutamate receptors. Thus, we summarize the importance of Ca2+ regulation in mammalian neurons and the excitotoxicity hypothesis, and focus on the molecular determinants of glutamate receptor-mediated excitotoxic mechanisms. (C) 2003 Elsevier Ltd. All rights reserved.