Nav1.7-A1632G mutation from a family with inherited erythromelalgia: Enhanced firing of dorsal root ganglia neurons evoked by thermal stimuli

Yang Yang, Jianying Huang, Malgorzata A. Mis, Mark Estacion, Lawrence Macala, Palak Shah, Betsy R. Schulman, Daniel B. Horton, Sulayman D. Dib-Hajj, Stephen G. Waxman

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


Voltage-gated sodium channel Nav1.7 is a central player in human pain. Mutations in Nav1.7 produce several pain syndromes, including inherited erythromelalgia (IEM), a disorder in which gain-of-function mutations render dorsal root ganglia (DRG) neurons hyperexcitable. Although patients with IEM suffer from episodes of intense burning pain triggered by warmth, the effects of increased temperature on DRG neurons expressing mutant Nav1.7 channels have not been well documented. Here, using structural modeling, voltage-clamp, current-clamp, and multielectrode array recordings, we have studied a newly identified Nav1.7 mutation, Ala1632Gly, from a multigeneration family with IEM. Structural modeling suggests that Ala1632 is a molecular hinge and that the Ala1632Gly mutation may affect channel gating. Voltage-clamp recordings revealed that the Nav1.7-A1632G mutation hyperpolarizes activation and depolarizes fastinactivation, both gain-of-function attributes at the channel level. Whole-cell current-clamp recordings demonstrated increased spontaneous firing, lower current threshold, and enhanced evoked firing in rat DRG neurons expressing Nav1.7-A1632G mutant channels. Multielectrode array recordings further revealed that intact ratDRGneurons expressing Nav1.7-A1632G mutant channels aremoreactive than those expressing Nav1.7 WT channels. We also showed that physiologically relevant thermal stimuli markedly increase the mean firing frequencies and the number of active rat DRG neurons expressing Nav1.7-A1632G mutant channels, whereas the same thermal stimuli only increase these parameters slightly in rat DRG neurons expressing Nav1.7 WT channels. The response of DRG neurons expressing Nav1.7-A1632G mutant channels upon increase in temperature suggests a cellular basis for warmth-triggered pain in IEM.

Original languageEnglish (US)
Pages (from-to)7511-7522
Number of pages12
JournalJournal of Neuroscience
Issue number28
StatePublished - Jul 13 2016

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)


  • Chronic pain
  • Man on fire syndrome
  • Sensory neurons
  • Temperature responses
  • Thermosensation
  • Voltage-gated sodium channel


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