Background and Purpose The voltage‐gated sodium channel Nav1.7 is essential for adequate perception of painful stimuli. Mutations in the encoding gene, SCN9A, cause various pain syndromes in humans. The hNav1.7/A1632E channel mutant causes symptoms of erythromelalgia and paroxysmal extreme pain disorder (PEPD), and its main gating change is a strongly enhanced persistent current. On the basis of recently published 3D structures of voltage‐gated sodium channels, we investigated how the inactivation particle binds to the channel, how this mechanism is altered by the hNav1.7/A1632E mutation, and how dimerization modifies function of the pain‐linked mutation. Experimental Approach We applied atomistic molecular simulations to demonstrate the effect of the mutation on channel fast inactivation. Native PAGE was used to demonstrate channel dimerization, and electrophysiological measurements in HEK cells and Xenopus laevis oocytes were used to analyze the links between functional channel dimerization and impairment of fast inactivation by the hNav1.7/A1632E mutation. Key Results Enhanced persistent current through hNav1.7/A1632E channels was caused by impaired binding of the inactivation particle, which inhibits proper functioning of the recently proposed allosteric fast inactivation mechanism. hNav1.7 channels form dimers and the disease‐associated persistent current through hNav1.7/A1632E channels depends on their functional dimerization status: Expression of the synthetic peptide difopein, a 14‐3‐3 inhibitor known to functionally uncouple dimers, decreased hNav1.7/A1632E channel‐induced persistent currents. Conclusion and Implications Functional uncoupling of mutant hNav1.7/A1632E channel dimers restored their defective allosteric fast inactivation mechanism. Our findings support the concept of sodium channel dimerization and reveal its potential relevance for human pain syndromes.

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