Calcium, neuronal hyperexcitability and ischemic injury.

Due to tight regulatory controls, a 10,000-fold concentration gradient exists between intracellular and extracellular free Ca2+ concentrations. With appropriate stimulus Ca2+ will rapidly flow into neurons through various types of membrane channels including voltage-dependent and receptor-operated channels. Intracellular Ca2+ concentrations are then quickly restored primarily through Ca2+-ATPase, Na+/Ca2+ exchange, and endoplasmic reticulum sequestration. It is well-known that Ca2+ is essential for neurotransmitter release. More recent investigations indicate that Ca2+ influx is essential for neuronal excitability independent from synaptic function. In fact, abnormal Ca2+ metabolism may play a dominant role in both the initiation and propagation of seizure discharge. Accordingly, Ca2+ channel blockers may represent a new therapeutic modality to treat epilepsy. Analyzed in this article are the major mechanisms by which neurons control Ca2+ fluxes and the evidence supporting the role of Ca2+ in seizure phenomena. Thereafter, an integrative theory for the role of calcium in neuronal hyperexcitability and ischemic cell death is constructed.