Page - (000274) - in Biomedical Chemistry: Current Trends and Developments

James J. Chambers* 3.2 Targeting Calcium-mediated Excitotoxicity in the CNS 3.2.1 Introduction At the heart of our ability to recognize, remember, and perform basic motor functions, is the highly coordinated placement of neuronal receptors at the interface between adjacent cells that control the flux of metal ions across the membrane (Kerchner & Nicoll, 2008; Ribrault, 2011; Wang, 2012). Glutamate is the neurotransmitter that mediates the majority of fast, excitatory neurotransmission in the central nervous system (Cotman & Monaghan, 1986). Vesicles of glutamate are released from the presynaptic cell when action potentials depolarize the membrane of synaptic boutons (terminals) and vesicles fuse with the membrane (Debelleroche & Bradford, 1977). Glutamate then diffuses across the synapse and activates postsynaptic glutamate receptors, initiating postsynaptic current flow via ion entry and depolarizing that cell, thus completing chemical synaptic communication (Moore & Buchanan, 1993). Despite decades of inquiry, we still do not fully understand the elegant electrical and chemical neuronal signals that are generated in a highly complex tangle of minuscule structures. Communication between cells in the nervous system requires neurons to quickly alter their membrane potential, transiently entering a depolarized, excited state to pass action potentials along to neighboring neurons, and then rapid repolarization to be prepared for new incoming information. Over-excitation of neurons by various means maintains a depolarized state for longer than usual and can contribute to neurological disease. Some of these diseases, which are linked to neuronal over-activity, can also cause cell damage and death via a process called excitotoxicity. Excitotoxicity is thought to play a role in neuronal cell and network damage following stroke and traumatic brain injury and, quite possibly, in the progressive damage associated with a