Molecular determinant of low-voltage dependence of human Nav1.7 inactivation revealed by efficacy-based Nav1.7 selective inhibitor.

Nav1.7 is a voltage-gated sodium channel (VGSC) subtype predominantly expressed in sensory neurons, amplifying threshold currents. Here, we identify that Uvarigranol D (UGD) suppresses human (h) Nav1.7 with a much greater maximal inhibition than other VGSC subtypes, despite having similar apparent affinities. We demonstrate that Thr1398 determines the greater inhibitory efficacy of UGD, the leftward shift in voltage-dependence and faster inactivation kinetics of hNav1.7. UGD binds to the inactivated state, with Gln360, Ile394, Lys1395, Phe1737, and Tyr1744 being critically involved. Moreover, while UGD suppresses action potentials in both rat dorsal root ganglion neurons and human induced pluripotent stem cell-derived cardiomyocytes, its ~60-fold greater sensitivity in neurons demonstrates that differences in maximal inhibition can translate into functional selectivity across excitable cells. We conclude that Thr1398 is critical to the unique function of hNav1.7 as a threshold current generator, and the lower voltage-dependence can be exploited for developing selective Nav1.7 inhibitors.