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⁺-ATP-ase, 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 dominent 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.