Page - (000291) - in Biomedical Chemistry: Current Trends and Developments

that blockage of these channels can prevent or delay cell death (Corona & Tapia, 2007; Van Damme, 2002; Van Den Bosch & Robberecht, 2000). In addition, the calcium-permeable AMPA receptor-mediated excitotoxicity can be delayed by chelation of calcium in models of ALS by application of BAPTA (Corona, 2007). Our present understanding of the molecular determinants of ALS progression all point to the involvement of calcium-permeable AMPA receptors and thus these ion channels warrant further study and targeting for new pharmacological agents. Of course, an alternative method to potentially reduce the expression of calcium-permeable AMPA receptors would be to restore the enzymatic activity of ADAR2, the enzyme responsible for editing the GluA2 RNA to make calcium-impermeable AMPA receptors. 3.2.9 Conclusions and Outlook With an increasingly large aging population, the numbers of people afflicted with the diseases of excitotoxicity will continue to grow. Treatment of the effects of calcium-mediated excitotoxicity should be at the forefront of our collective efforts to treat these diseases. In too few cases, there are obvious genetic targets that can potentially be addressed with the new genome editing technology that is currently maturing. However, for the vast majority of sporadic cases of disease, the root cause is either undetected genomic mutations or environmental or developmental insults. For these categories, genome editing has no known target and thus, must be tackled at the site of molecular damage. With calcium-mediated excitotoxicity implicated in so many neurological diseases, the prize for the scientist who solves this problem will likely be substantial and society will be indebted to them. References Araki, Y., Lin, D. T., Huganir, R. L. (2010). Plasma membrane insertion of the AMPA receptor GluA2 subunit is regulated by NSF binding and Q/R editing of the ion pore. Proceedings of the National Academy of Sciences, 107, 11080-11085. Ballard, C., Gauthier, S., Corbett, A., (2011). Alzheimer’s disease. Lancet, 377, 1019-1031. Beique, J. C., Na, Y., Kuhl, D., (2011). Arc-dependent synapse-specific homeostatic plasticity.