Inhibition of the cloned delayed rectifier K⁺ channels, Kv1.5 and Kv3.1, by riluzole

The action of riluzole, a neuroprotective drug, on cloned delayed rectifier K⁺ channels (Kv1.5 and Kv3.1) was examined using the whole-cell patch-clamp technique. Riluzole reversibly inhibited Kv1.5 currents in a concentration-dependent manner with an IC₅₀ of 39.69±2. 37μM. G-protein inhibitors (pertussis toxin and GDPβS) did not prevent this inhibition of riluzole on Kv1.5. No voltage-dependent inhibition by riluzole was found over the voltage range in which channels are fully activated. Riluzole shifted the steady-state inactivation curves of Kv1.5 in a hyperpolarizing direction in a concentration-dependent manner. It accelerated the deactivation kinetics of Kv1.5 in a concentration dependent-manner, but had no effect on the steady-state activation curve. Riluzole exhibited a use-independent inhibition of Kv1.5. The effects of riluzole on Kv3.1, the Shaw-type K⁺ channel were also examined. Riluzole caused a concentration-dependent inhibition of Kv3.1 currents with an IC₅₀ of 120.98±9.74μM and also shifted the steady-state inactivation curve of Kv3.1 in the hyperpolarizing direction. Thus, riluzole inhibits both Kv1.5 and Kv3.1 currents in a concentration-dependent manner and interacts directly with Kv1.5 by preferentially binding to the inactivated and to the closed states of the channel.