Properties of human brain sodium channel α-subunits expressed in HEK293 cells and their modulation by carbamazepine, phenytoin and lamotrigine

BACKGROUND AND PURPOSE:
Voltage-activated Na+ channels contain one distinct alpha-subunit; in the brain NaV 1.1, NaV 1.2, NaV 1.3 and NaV 1.6 are the four most abundantly expressed alpha-subunits. The antiepileptic drugs (AEDs) carbamazepine (CBZ), phenytoin (DPH) and lamotrigine (LTG) have voltage-gated Na+ channels as their primary therapeutic targets. This study provides a systematic comparison of the biophysical properties of these four alpha-subunits and characterizes their interaction with CBZ, DPH and LTG. EXPERIMENTAL APPROACH:
Na+ currents were recorded in voltage-clamp mode in HEK293 cells stably expressing one of the four alpha-subunits.
KEY RESULTS:
NaV 1.2 and NaV 1.3 subunits have a relatively slow recovery from inactivation as compared to the other subunits. The NaV 1.1 subunit generates the largest window current. LTG evokes a larger maximal shift of the steady-state inactivation relationship than CBZ or DPH. CBZ shows the highest binding rate to the alpha-subunits. LTG binding to the NaV 1.1 subunit is faster than to the other alpha-subunits. LTG unbinding from the alpha-subunits is slower than that of CBZ and DPH.
CONCLUSIONS AND IMPLICATIONS:
The four Na+ channel alpha-subunits show subtle differences in their biophysical properties, which, in combination with their (sub)cellular expression patterns in the brain, could contribute to differences in neuronal excitability. We also observed differences in the parameters that characterize AED binding to the Na+ channel subunits. Particularly, LTG binding to the four alpha-subunits suggests a subunit-specific response. Such differences will have consequences for the clinical efficacy of AEDs. But knowledge about biophysical and binding parameters could also be employed to optimize therapeutic strategies and drug development.