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

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

  • Nat Commun. 2026 Feb 10;17(1):2559. doi: 10.1038/s41467-026-69184-8.
Fang Zhao 1 2,  Chuchu Xi 1 2,  Jie Li 1,  Kerui Ren 1,  Qinglian Tang 1,  Huaduan Liang 1,  Shilong Yang 3,  Michael X Zhu 4,  Zhengyu Cao 5 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
  • 2 Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
  • 3 College of Wildlife and Protected Area, Northeast Forestry University, Harbin, Heilongjiang, 150040, China.
  • 4 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. [email protected].
  • 5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China. [email protected].
  • 6 Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China. [email protected].
PMID: 41667447 DOI: 10.1038/s41467-026-69184-8
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.

Figures
Products