The voltage-gated sodium channel Nav1.7 is essential for an adequate perception of painful stimuli. Its mutations cause various pain syndromes in human patients. The hNav1.7/A1632E mutation induces symptoms of erythromelalgia and paroxysmal extreme pain disorder (PEPD), and its main gating change is a strongly enhanced persistent current.Using molecular simulations, we demonstrate that the disease causing persistent current of hNav1.7/A1632E is due to impaired binding of the IFM motif, thus affecting proper function of the recently proposed allosteric fast inactivation mechanism. By using native polyacrylamide gel electrophoresis (PAGE) gels, we show that hNav1.7 dimerizes. The disease-linked persistent current depends on the channel’s functional dimerization status: Using difopein, a 14-3-3 inhibitor known to uncouple dimerization of hNav1.5, we detect a significant decrease in hNav1.7/A1632E induced persistent currents.Our work identifies that functional uncoupling of hNav1.7/A1632E dimers rescues the pain-causing molecular phenotype by interferes with an allosteric fast inactivation mechanism, which we link for the first time to channel dimerization. Our work supports the concept of sodium channel dimerization and reveals its relevance to human pain syndromes.

channel b-subunit genes revealed a mutation in the SCN2B gene, which we have functionally tested. Current-clamp analysis revealed that this mutant b2 subunit rendered small-diameter dorsal root ganglion (DRG) neurons hyperexcitable compared to DRG neurons expressing the wild-type b2 subunit. Additionally, b-subunits are known to increase sodium current density and alter biophysical properties of sodium channels. Voltageclamp analysis of small DRG neurons expressing the variant b2 subunit showed increased total sodium current density. As b-subunits can interact with all Na v channels, we subsequently investigated the effect of this mutation on TTXsensitive vs. TTX-resistant sodium channels. Results of this analysis and on the effect of the expression of the mutant b-subunit on gating properties of sodium channels will be presented.