Mechanism of the persistent sodium current activator veratridine-evoked Ca2+ elevation: implication for epilepsy

Although the role of Na⁺ in several aspects of Ca²⁺ regulation has already been shown, the exact mechanism of intracellular Ca²⁺ concentration (Ca²⁺]_i) increase resulting from an enhancement in the persistent, non‐inactivating Na⁺ current (I_Na,P), a decisive factor in certain forms of epilepsy, has yet to be resolved. Persistent Na⁺ current, evoked by veratridine, induced bursts of action potentials and sustained membrane depolarization with monophasic intracellular Na⁺ concentration (Na⁺]_i) and biphasic Ca²⁺]_i increase in CA1 pyramidal cells in acute hippocampal slices. The Ca²⁺ response was tetrodotoxin‐ and extracellular Ca²⁺‐dependent and ionotropic glutamate receptor‐independent. The first phase of Ca²⁺]_i rise was the net result of Ca²⁺ influx through voltage‐gated Ca²⁺ channels and mitochondrial Ca²⁺ sequestration. The robust second phase in addition involved reverse operation of the Na⁺–Ca²⁺ exchanger and mitochondrial Ca²⁺ release. We excluded contribution of the endoplasmic reticulum. These results demonstrate a complex interaction between persistent, non‐inactivating Na⁺ current and Ca²⁺]_i regulation in CA1 pyramidal cells. The described cellular mechanisms are most likely part of the pathomechanism of certain forms of epilepsy that are associated with I_Na,P. Describing the magnitude, temporal pattern and sources of Ca²⁺ increase induced by I_Na,P may provide novel targets for antiepileptic drug therapy.