PT - JOURNAL ARTICLE AU - Ging Kuo Wang AU - Sho-Ya Wang TI - Block of Human Cardiac Sodium Channels by Lacosamide: Evidence for Slow Drug Binding Along the Activation Pathway AID - 10.1124/mol.113.091173 DP - 2014 Feb 21 TA - Molecular Pharmacology PG - mol.113.091173 4099 - http://molpharm.aspetjournals.org/content/early/2014/02/21/mol.113.091173.short 4100 - http://molpharm.aspetjournals.org/content/early/2014/02/21/mol.113.091173.full AB - Lacosamide is an anticonvulsant hypothesized to enhance slow inactivation of neuronal Na+ channels for its therapeutic action. Cardiac Na+ channels display less and incomplete slow inactivation but their sensitivity toward lacosamide remains unknown. We therefore investigated the action of lacosamide in human cardiac Nav1.5 and Nav1.5-CW inactivation-deficient Na+ channels. Lacosamide showed little effects on hNav1.5 Na+ currents at 300 μM when cells were held at -140 mV. With 30-s conditioning pulses from -90 mV to -50 mV, however, hNav1.5 Na+ channels became sensitive to lacosamide with IC50 (50% inhibitory concentration) around 70-80 μM. Higher IC50 values were found at -110 mV and -30 mV. The development of lacosamide block at ‒70 mV was slow in wild-type Na+ channels (τ; 8.04 ±0.39 s, n = 8). This time constant was significantly accelerated in hNav1.5-CW inactivation-deficient counterparts. The recovery from lacosamide block at -70 mV for 10 s was relatively rapid in wild-type Na+ channels (τ; 639 ±90 ms, n = 8). This recovery was accelerated further in hNav1.5-CW counterparts. Unexpectedly, lacosamide elicited a time-dependent block of persistent hNav1.5-CW Na+ currents with an IC50 of 242 ±19 μM (n = 5). Furthermore, both hNav1.5-CW/F1760K mutant and batrachotoxin-activated hNav1.5 Na+ channels became completely lacosamide resistant, indicating that the lacosamide receptor overlaps receptors for local anesthetics and batrachotoxin. Our results together suggest that lacosamide targets the intermediate pre-open and open states of hNav1.5 Na+ channels. Lacosamide may thus track closely the conformational changes at the hNav1.5-F1760 region along the activation pathway.