Faculty, Staff and Student Publications
Language
English
Publication Date
2-10-2026
Journal
Nature Communications
DOI
10.1038/s41467-026-69184-8
PMID
41667447
PMCID
PMC13000156
PubMedCentral® Posted Date
2-10-2026
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
NAV1.7 Voltage-Gated Sodium Channel, Humans, Animals, Ganglia, Spinal, Rats, Myocytes, Cardiac, Induced Pluripotent Stem Cells, Action Potentials, Voltage-Gated Sodium Channel Blockers, HEK293 Cells, Neurons, Ion channels in the nervous system, Neuropathic pain, Ion channels, Permeation and transport
Published Open-Access
yes
Recommended Citation
Zhao, Fang; Xi, Chuchu; Li, Jie; et al., "Molecular Determinant of Low-Voltage Dependence of Human Nav1.7 Inactivation Revealed by Efficacy-Based Nav1.7 Selective Inhibitor" (2026). Faculty, Staff and Student Publications. 3493.
https://digitalcommons.library.tmc.edu/uthmed_docs/3493