Uncoupling sodium channel dimers rescues phenotype of pain-linked Nav1.7 mutation

Ruehlmann, A.; Koerner, J.; Bebrivenski, N.; Detro-Dassen, S.; Hautvast, P.; Benasolo, C. A.; Meents, J.; Machtens, J.-P.; Schmalzing, G.; Lampert, A.

doi:10.1101/716654

bioRxiv · 10.1101/716654

Uncoupling sodium channel dimers rescues phenotype of pain-linked Nav1.7 mutation

Ruehlmann, A.·Koerner, J.·Bebrivenski, N.·Detro-Dassen, S.·Hautvast, P.·Benasolo, C. A.·Meents, J.·Machtens, J.-P.·Schmalzing, G.·Lampert, A.

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Abstract

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.\n\nUsing 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 channels 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.\n\nOur 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.

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Ruehlmann, A., Koerner, J., Bebrivenski, N., Detro-Dassen, S., Hautvast, P., Benasolo, C. A., Meents, J., Machtens, J.-P., Schmalzing, G., Lampert, A.. 2019-07-27. Uncoupling sodium channel dimers rescues phenotype of pain-linked Nav1.7 mutation. https://doi.org/10.1101/716654

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