A disease mutation reveals a role for NaV1.9 in acute itch

J Clin Invest. 2018 Dec 3;128(12):5434-5447. doi: 10.1172/JCI122481. Epub 2018 Nov 5.


Itch (pruritis) and pain represent two distinct sensory modalities; yet both have evolved to alert us to potentially harmful external stimuli. Compared with pain, our understanding of itch is still nascent. Here, we report a new clinical case of debilitating itch and altered pain perception resulting from the heterozygous de novo p.L811P gain-of-function mutation in NaV1.9, a voltage-gated sodium (NaV) channel subtype that relays sensory information from the periphery to the spine. To investigate the role of NaV1.9 in itch, we developed a mouse line in which the channel is N-terminally tagged with a fluorescent protein, thereby enabling the reliable identification and biophysical characterization of NaV1.9-expressing neurons. We also assessed NaV1.9 involvement in itch by using a newly created NaV1.9-/- and NaV1.9L799P/WT mouse model. We found that NaV1.9 is expressed in a subset of nonmyelinated, nonpeptidergic small-diameter dorsal root ganglia (DRGs). In WT DRGs, but not those of NaV1.9-/- mice, pruritogens altered action potential parameters and NaV channel gating properties. Additionally, NaV1.9-/- mice exhibited a strong reduction in acute scratching behavior in response to pruritogens, whereas NaV1.9L799P/WT mice displayed increased spontaneous scratching. Altogether, our data suggest an important contribution of NaV1.9 to itch signaling.

Keywords: Genetic diseases; Ion channels; Neuroscience.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Ganglia, Spinal* / metabolism
  • Ganglia, Spinal* / pathology
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mutation*
  • NAV1.9 Voltage-Gated Sodium Channel* / genetics
  • NAV1.9 Voltage-Gated Sodium Channel* / metabolism
  • Neurons* / metabolism
  • Neurons* / pathology
  • Pruritus* / genetics
  • Pruritus* / metabolism
  • Pruritus* / pathology
  • Signal Transduction*


  • NAV1.9 Voltage-Gated Sodium Channel
  • SCN11A protein, human
  • Scn11a protein, mouse