Block of the rat brain IIA sodium channel alpha subunit by the neuroprotective drug riluzole.

The effects of riluzole, a novel neuroprotective drug with anticonvulsant and anti-ischemic properties, were studied on currents carried by cloned rat brain IIA sodium channel alpha subunits expressed in Xenopus oocytes. (i) When the oocytes were held at strongly hyperpolarized potentials to close the sodium channels and riluzole was added to the external solution, the current elicited by test depolarizing pulses was reduced within a few minutes and recovered upon washout of the riluzole. Although the currents were reduced, riluzole did not shift the peak current-voltage relationship. An inhibitory constant of 30 microM was estimated for the low affinity block of closed channels. (ii) Riluzole did not affect the time course of inactivation, and repetitive stimulation at frequencies that did not result in significant accumulation of inactivation did not affect current block. These results suggest that riluzole did not block open channels. (iii) Riluzole increased steady state inactivation by shifting its voltage dependence in the hyperpolarizing direction, by prolonging the recovery from inactivation, and by blocking more effectively at high stimulation frequencies. According to the modulated receptor theory, these results suggest that riluzole binds selectively to inactivated channels, with an inhibitory constant estimated at 0.2 microM. These results show that the riluzole binding site is on the alpha subunit of the sodium channel, and they suggest that stabilization of the inactivated state may underlie the neuroprotective properties of riluzole.