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

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

Author information

1
Department of Physiology.
2
Solomon H. Snyder Department of Neuroscience.
3
Department of Psychiatry and Behavioral Sciences, and.
4
Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
5
Department of Basic and Applied Medical Sciences, Ghent University, Ghent, Belgium.

Abstract

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

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