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A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons

  1. Anthony M. Rush * , † ,
  2. Sulayman D. Dib-Hajj * , † ,
  3. Shujun Liu * , † ,
  4. Theodore R. Cummins ‡ ,
  5. Joel A. Black * , † , and
  6. Stephen G. Waxman * , † , §
  1. *Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510;
  2. †Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare Center, West Haven, CT 06516; and
  3. ‡Department of Pharmacology and Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202

  1. Communicated by Dominick P. Purpura, Albert Einstein College of Medicine, Bronx, NY, April 6, 2006 (received for review February 1, 2006)

Abstract

Disease-producing mutations of ion channels are usually characterized as producing hyperexcitability or hypoexcitability. We show here that a single mutation can produce hyperexcitability in one neuronal cell type and hypoexcitability in another neuronal cell type. We studied the functional effects of a mutation of sodium channel Nav1.7 associated with a neuropathic pain syndrome, erythermalgia, within sensory and sympathetic ganglion neurons, two cell types where Nav1.7 is normally expressed. Although this mutation depolarizes resting membrane potential in both types of neurons, it renders sensory neurons hyperexcitable and sympathetic neurons hypoexcitable. The selective presence, in sensory but not sympathetic neurons, of the Nav1.8 channel, which remains available for activation at depolarized membrane potentials, is a major determinant of these opposing effects. These results provide a molecular basis for the sympathetic dysfunction that has been observed in erythermalgia. Moreover, these findings show that a single ion channel mutation can produce opposing phenotypes (hyperexcitability or hypoexcitability) in the different cell types in which the channel is expressed.

Footnotes

  • §To whom correspondence should be addressed at:
    Department of Neurology, LCI 707, Yale Medical School, P.O. Box 208018, New Haven, CT 06520.
    E-mail: stephen.waxman{at}yale.edu

  • Author contributions: A.M.R., S.D.D.-H., T.R.C., and S.G.W. designed research; A.M.R., S.D.D.-H., S.L., and J.A.B. performed research; A.M.R., S.D.D.-H., J.A.B., and S.G.W. analyzed data; and A.M.R., S.D.D.-H., J.A.B., and S.G.W. wrote the paper.

  • Conflict of interest statement: No conflicts declared.

  • Abbreviations:

    Abbreviations:

    DRG,
    dorsal root ganglion/ganglia;
    SCG,
    superior cervical ganglion/ganglia;
    RMP,
    resting membrane potential.

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