Nav1.7 mutations associated with paroxysmal extreme pain disorder, but not erythromelalgia, enhance Navβ4 peptide-mediated resurgent sodium currents

Jonathan W. Theile, Brian W. Jarecki, Andrew D. Piekarz, Theodore Cummins

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Abstract

Inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD) are inherited pain syndromes predominantly caused by missense mutations in the peripheral neuronal voltage-gated sodium channel (Nav) isoform Nav1.7. While both IEM and PEPD mutations increase neuronal excitability, IEM mutations primarily enhance activation and PEPD mutations impair inactivation. In addition, one PEPD mutation, Nav1.7-I1461T, has been shown to increase resurgent sodium currents in dorsal root ganglion (DRG) neurons. Because resurgent currents have been implicated in increased neuronal excitability, we asked whether (1) additional PEPD mutations located within the putative inactivation gate and docking sites and (2) IEM mutations might also increase these unusual currents. Resurgent currents are generated following open-channel block at positive potentials by an endogenous blocking particle and subsequent expulsion of this blocker upon repolarization to moderately negative potentials. Here we used a mimetic of the putative blocking particle, the Navβ4 peptide, to determine if enhanced resurgent currents are induced by three distinct PEPD mutations and two IEM mutations in stably transfected HEK293 cells. We demonstrate that (1) Nav1.7-mediated resurgent currents are observed in HEK293 cells with the Navβ4 peptide in the recording pipette, (2) while the PEPD mutants M1627K, T1464I and V1299F exhibit enhanced resurgent current amplitudes compared to wild-type, the IEM mutants I848T and L858H do not, and (3) there is a strong correlation between the decay time constant of open-channel fast inactivation and resurgent current amplitude. These data suggest that resurgent currents may play a role in the neuronal hyperexcitability associated with PEPD, but not IEM, mutations.

Original languageEnglish
Pages (from-to)597-608
Number of pages12
JournalJournal of Physiology
Volume589
Issue number3
DOIs
StatePublished - Feb 2011

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Erythromelalgia
Sodium
Peptides
Mutation
HEK293 Cells
Voltage-Gated Sodium Channels
Paroxysmal Extreme Pain Disorder
Spinal Ganglia
Missense Mutation
Protein Isoforms

ASJC Scopus subject areas

  • Physiology

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Nav1.7 mutations associated with paroxysmal extreme pain disorder, but not erythromelalgia, enhance Navβ4 peptide-mediated resurgent sodium currents. / Theile, Jonathan W.; Jarecki, Brian W.; Piekarz, Andrew D.; Cummins, Theodore.

In: Journal of Physiology, Vol. 589, No. 3, 02.2011, p. 597-608.

Research output: Contribution to journalArticle

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