A disease mutation reveals a role for NaV1.9 in acute itch
Juan Salvatierra, … , Xinzhong Dong, Frank Bosmans
Juan Salvatierra, … , Xinzhong Dong, Frank Bosmans
Published December 3, 2018; First published November 5, 2018
Citation Information: J Clin Invest. 2018;128(12):5434-5447. https://doi.org/10.1172/JCI122481.
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Research Article Neuroscience

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

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.

Authors

Juan Salvatierra, Marcelo Diaz-Bustamante, James Meixiong, Elaine Tierney, Xinzhong Dong, Frank Bosmans

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