title: Block of human cardiac sodium channels by lacosamide: evidence for slow drug binding along the activation pathway.
abstract: 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 effect on hNav1.5 Na(+) currents at 300 µM when cells were held at -140 mV. With 30-second conditioning pulses from -90 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 and -30 mV. The development of lacosamide block at -70 mV was slow in wild-type Na(+) channels (τ; 8.04 ± 0.39 seconds, 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 seconds was relatively rapid in wild-type Na(+) channels (τ; 639 ± 90 milliseconds, 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 preopen 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.
authors.affiliation: Department of Anesthesiology, Perioperative, Pain Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts (G.K.W.); and Department of Biological Sciences, SUNY at Albany, Albany, New York (S.-Y.W.).
authors.forename: Ging Kuo
authors.initials: GK
authors.lastname: Wang
authors.forename: Sho-Ya
authors.initials: SY
authors.lastname: Wang
mesh_terms: D000081:Acetamides / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D000078334:Lacosamide; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000378:metabolism* / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000081:Acetamides; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D000078334:Lacosamide