Lacosamide inhibition of Nav1.7 voltage-gated sodium channels: Slow binding to fast-inactivated states

Abstract

Lacosamide is an antiseizure agent that targets voltagedependent sodium channels. Previous experiments have suggested that lacosamide is unusual in binding selectively to the slow-inactivated state of sodium channels, in contrast to drugs like carbamazepine and phenytoin, which bind tightly to fast-inactivated states. Using heterologously expressed human Nav1.7 sodium channels, we examined the state-dependent effects of lacosamide. Lacosamide induced a reversible shift in the voltage dependence of fast inactivation studied with 100-millisecond prepulses, suggesting binding to fast-inactivated states. Using steady holding potentials, lacosamide block was very weak at - 120 mV (3% inhibition by 100 μM lacosamide) but greatly enhanced at 2 80 mV (43% inhibition by 100 mM lacosamide), where there is partial fast inactivation but little or no slow inactivation. During long depolarizations, lacosamide slowly (over seconds) put channels into states that recovered availability slowly (hundreds of milliseconds) at - 120 mV. This resembles enhancement of slow inactivation, but the effect was much more pronounced at - 40 mV, where fast inactivation is complete, but slow inactivation is not, than at 0 mV, where slow inactivation is maximal, more consistent with slow binding to fast-inactivated states than selective binding to slowinactivated states. Furthermore, inhibition by lacosamide was greatly reduced by pretreatment with 300 μMlidocaine or 300 μM carbamazepine, suggesting that lacosamide, lidocaine, and carbamazepine all bind to the same site. The results suggest that lacosamide binds to fast-inactivated states in a manner similar to other antiseizure agents but with slower kinetics of binding and unbinding.