In:
Frontiers in Pharmacology, Frontiers Media SA, Vol. 12 ( 2021-12-21)
Abstract:
Lacosamide, developed as an anti-epileptic drug, has been used for the treatment of pain. Unlike typical anticonvulsants and local anesthetics which enhance fast-inactivation and bind within the pore of sodium channels, lacosamide enhances slow-inactivation of these channels, suggesting different binding mechanisms and mode of action. It has been reported that lacosamide’s effect on Na V 1.5 is sensitive to a mutation in the local anesthetic binding site, and that it binds with slow kinetics to the fast-inactivated state of Na V 1.7. We recently showed that the Na V 1.7-W1538R mutation in the voltage-sensing domain 4 completely abolishes Na V 1.7 inhibition by clinically-achievable concentration of lacosamide. Our molecular docking analysis suggests a role for W1538 and pore residues as high affinity binding sites for lacosamide. Aryl sulfonamide sodium channel blockers are also sensitive to substitutions of the W1538 residue but not of pore residues. To elucidate the mechanism by which lacosamide exerts its effects, we used voltage-clamp recordings and show that lacosamide requires an intact local anesthetic binding site to inhibit Na V 1.7 channels. Additionally, the W1538R mutation does not abrogate local anesthetic lidocaine-induced blockade. We also show that the naturally occurring arginine in Na V 1.3 (Na V 1.3-R1560), which corresponds to Na V 1.7-W1538R, is not sufficient to explain the resistance of Na V 1.3 to clinically-relevant concentrations of lacosamide. However, the Na V 1.7-W1538R mutation conferred sensitivity to the Na V 1.3-selective aryl-sulfonamide blocker ICA-121431. Together, the W1538 residue and an intact local anesthetic site are required for lacosamide’s block of Na V 1.7 at a clinically-achievable concentration. Moreover, the contribution of W1538 to lacosamide inhibitory effects appears to be isoform-specific.
Type of Medium:
Online Resource
ISSN:
1663-9812
DOI:
10.3389/fphar.2021.791740
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2021
detail.hit.zdb_id:
2587355-6
SSG:
15,3
