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,I-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,I-P. Describing the magnitude, temporal pattern and sources of Ca2+ increase induced by I-Na,I-P may provide novel targets for antiepileptic drug therapy.