Mechanism of the persistent sodium current activator veratridine-evoked Ca elevation: implication for epilepsy.

Although the role of Na(+) in several aspects of Ca(2+) regulation has already been shown, the exact mechanism of intracellular Ca(2+) concentration ([Ca(2+)](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 [Ca(2+)](i) increase in CA1 pyramidal cells in acute hippocampal slices. The Ca(2+) response was tetrodotoxin- and extracellular Ca(2+)-dependent and ionotropic glutamate receptor-independent. The first phase of [Ca(2+)](i) rise was the net result of Ca(2+) influx through voltage-gated Ca(2+) channels and mitochondrial Ca(2+) sequestration. The robust second phase in addition involved reverse operation of the Na(+)-Ca(2+) exchanger and mitochondrial Ca(2+) release. We excluded contribution of the endoplasmic reticulum. These results demonstrate a complex interaction between persistent, non-inactivating Na(+) current and [Ca(2+)](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 Ca(2+) increase induced by I(Na,P) may provide novel targets for antiepileptic drug therapy.