Analytical studies of rapidly inactivating and noninactivating sodium currents in differentiated NG108-15 neuronal...

The rapidly inactivating (I(Naf)) and noninactivating Na(+) currents (I(Na)(()(NI)())) were characterized in NG108-15 neuronal cells differentiated with dibutyryl cyclic AMP in this study. Standard activation and inactivation protocols were used to evaluate the steady-state and kinetic properties of the I(Naf) present in these cells. The voltage protocols with a slowly depolarizing ramp were implemented to examine the properties of I(Na)(()(NI)()). Based on experimental data and computer simulations, a window component of the rapidly inactivating sodium current (I(Naf)(()(W)())) was also generated in response to the slowly depolarizing ramp. The I(Naf)(()(W)()) was subtracted from I(Na)(()(NI)()) to yield the persistent Na(+) current (I(Na)(()(P)())). Our results demonstrate the presence of I(Na)(()(P)()) in these cells. In addition to modifying the steady-state inactivation of I(Naf), ranolazine or riluzloe could be effective in blocking I(Naf)(()(W)()) and I(Na)(()(P)()). The ability of ranolazine and riluzole to suppress I(Na)(()(P)()) was greater than their ability to inhibit I(Naf)(()(W)()). In current-clamp recordings, current-induced voltage oscillations were applied to elicit action potentials (APs) through a gradual transition between spontaneous depolarization and upstroke. Ranolazine or riluzole at a concentration of 3 microM then effectively suppressed the AP firing generated by oscillatory changes in membrane current. The data suggest that a small rise in I(Na)(()(NI)()) facilitates neuronal hyper-excitability due the decreased threshold of AP initiation. The underlying mechanism of the inhibitory actions of ranolazine or riluzole on membrane potential in neurons or neuroendocrine cells in vivo may thus be associated with their blocking of I(Na)(()(NI)()).