Calcium, ischemia and excitotoxicity.
The initial reports regarding a cytotoxic role of calcium ions were published over 30 years ago. In neurons, calcium ions can gain entry into the cell through several mechanisms. These include the over-activation of glutamate receptors (NMDA, AMPA, KA) or of a range of channels and transporters (TRPM2, TRPM7, NCX, ASICs, CaV1.2, and hemichannels). Potentially toxic cytoplasmic calcium concentrations can also occur due to release from internal stores, either through physical damage to mitochondria and the endoplasmic reticulum, or a malfunction of receptors and channels present in their membranes. Such increases of cytoplasmic calcium concentrations can trigger a range of downstream neurotoxic cascades, including the uncoupling mitochondrial electron transfer from ATP synthesis, and the activation and overstimulation of enzymes such as calpains and other proteases, protein kinases, nitric oxide synthase (NOS), calcineurin and endonucleases. Despite the toxic role of calcium, drugs designed to block its entry into neurons have all failed to have any beneficial effects in clinical trials. We suggest that blocking certain receptors and ion channels is unlikely to be a useful therapeutic strategy due to potential deleterious side effects. However, identifying those that are most responsible for cell death and their downstream signalling pathways may lead to improved strategies for treating ischemic and excitotoxic disorders.
Szydlowska
Kinga
K
Toronto Western Hospital Research Institute, MC11-414, 399 Bathurst Street, Toronto, Ontario, Canada M5T2S8.
Tymianski
Michael
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D016923:Cell Death; D004579:Electron Transport; D006801:Humans; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism
D026901:Membrane Transport Proteins; D017470:Receptors, Glutamate; D019001:Nitric Oxide Synthase; D010447:Peptide Hydrolases; D002118:Calcium