Molecular determinant of low-voltage dependence of human Na(v)1.7 inactivation revealed by efficacy-based Na(v)1.7 selective inhibitor.

Na(v)1.7 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) Na(v)1.7 with a much greater maximal inhibition than other VGSC subtypes, despite having similar apparent affinities. We demonstrate that Thr(1398) determines the greater inhibitory efficacy of UGD, the leftward shift in voltage-dependence and faster inactivation kinetics of hNa(v)1.7. UGD binds to the inactivated state, with Gln(360), Ile(394), Lys(1395), Phe(1737), and Tyr(1744) 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 Thr(1398) is critical to the unique function of hNa(v)1.7 as a threshold current generator, and the lower voltage-dependence can be exploited for developing selective Na(v)1.7 inhibitors.