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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Categories: 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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Figure 3

NaV1.9 expression in MrgprA3+ and MrgprC11+ neurons and behavioral models.

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NaV1.9 expression in MrgprA3+ and MrgprC11+ neurons and behavioral model...
(A) Schematic diagram of the breeding strategy for the MrgprA3-EGFP-CretdTomato/+ mice showing tdTomato signal (fluorescence was visualized directly without staining). (B) Trace showing NaV1.9 currents evoked in tdTomato+ neurons at the specified voltages. (C) DRG section showing the overlap between neurons stained for GFP and MrgprC11. (D) DRG section illustrating the overlap between neurons stained for GPF and substance P. (E–G) Itch assays with the indicated compound injected into the nape of the neck, recorded for 30-minute intervals, performed in NaV1.9–/– mice and littermate controls for histamine (E; 8 mice per genotype, P = 0.02), CQ (F; 12 mice per genotype, P = 0.006), and BAM8-22 (G; WT n = 11, NaV1.9–/– n = 8, P = 0.002). Panels located directly below each graph (E–G) are the data binned and graphed for every 5 minutes of the recording. *P < 0.05, **P < 0.01, by 2-tailed, unpaired Student’s t test. Data are represented as mean ± SEM. Scale bars: 50 μm.