Key result
Nav1.7 mutations associated with paroxysmal extreme pain disorder, but not inherited erythromelalgia, enhance Navβ4 peptide-mediated resurgent sodium currents.
Nav1.7 mutations associated with PEPD enhance resurgent sodium currents, suggesting a specific mechanism for pain generation in this disorder.
Supports PEPD-specific resurgent current mechanism; leaves open human translation and therapeutic targeting.
Abnormal pain sensitivity associated with inherited and acquired pain disorders occurs through increased excitability of peripheral sensory neurons in part due to changes in the properties of voltage-gated sodium channels (Navs). Resurgent sodium currents (I(NaR)) are atypical currents believed to be associated with increased excitability of neurons and may have implications in pain. Mutations in Nav1.7 (peripheral Nav isoform) associated with two genetic pain disorders, inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD), enhance Nav1.7 function via distinct mechanisms. We show that changes in Nav1.7 function due to mutations associated with PEPD, but not IEM, are important in I(NaR) generation, suggesting that I(NaR) may play a role in pain associated with PEPD. This knowledge provides us with a better understanding of the mechanism of I(NaR) generation and may lead to the development of specialized treatment for pain disorders associated with I(NaR).
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Theile et al. (2010) studied Inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). Nav1.7 mutations associated with PEPD vs. Nav1.7 mutations associated with IEM was evaluated on Navβ4 peptide-mediated resurgent sodium currents (I(NaR)) generation. Nav1.7 mutations associated with paroxysmal extreme pain disorder, but not inherited erythromelalgia, enhance Navβ4 peptide-mediated resurgent sodium currents.
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