The inhibitory actions by lacosamide, a functionalized amino acid, on voltage-gated Na+ currents

- The ionic effect of lacosamide is investigated and simulated.
- Lacosamide blocks voltage-gated Na+ current in a frequency- and concentration-dependent manner in neurons.
- Lacosamide increases the inactivation space of Na+ channel states, shaping the adaptive neuronal response to previous firing.
- The non-inactivating Na+ and delayed-rectifier K+ current are not affected by lacosamide.
- Lacosamide attenuates the Na+ current in HEK293T cells expressing SCN5A, in a concentration-dependent fashion.

The effect of lacosamide (LCS), a functionalized molecule with anti-convulsant properties, on ion channels was investigated, with the aid of patch clamp technology and simulation modeling. In NSC-34 neuronal cells, LCS was found to block voltage-gated Na+ current (INa) in a frequency- and concentration-dependent manner. With the two-step voltage protocol, a minimal change in the steady-state inactivation of INa was found in the presence of LCS. However, with repetitive stimulation, the pulse-to-pulse reduction in peak current was shown to be exponential, with a rate linearly related to both the inter-stimulus interval and the LCS concentration. In addition, the frequency-dependent blocking properties were modeled by considering the drug interaction with a voltage-dependent mixture of NaV channels harboring either an accessible or an inaccessible binding site. LCS also increased the dimension of inactivation space of NaV-channel states, thereby producing the adaptive response of neurons to previous firing. LCS (30 μM) had no effects on the non-inactivating component of INa, while it slightly decreased the amplitude of delayed-rectifier K+ current. Moreover, LCS suppressed the peak amplitude of INa in embryonic cortical neurons. In human embryonic kidney (HEK293T) cells which expressed SCN5A, LCS attenuated the peak amplitude of INa, in a concentration-dependent fashion. The unique effects of LCS on NaV currents presented here may contribute to its in vivo modulation of cellular excitability.