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 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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Figure 4

Loss of NaV1.9 leads to a reduction in histamine- and CQ-responsive but not BAM8-22–responsive neurons.

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Loss of NaV1.9 leads to a reduction in histamine- and CQ-responsive but ...
Fura-2 ratiometric Ca2+ imaging studies were performed in NaV1.9–/– mice and littermate controls. The total percentage of responsive neurons and the magnitude of the Ca2+ response were quantified, and representative traces for the Ca2+ response after application of each compound are shown. For histamine, the total percentage of responsive neurons was reduced (A; WT and NaV1.9–/– n ≥ 800 cells, P = 0.0014), but the magnitude of the response was the same in WT and NaV1.9–/– neurons (B; WT and NaV1.9–/– n ≥ 800 cells, P = 0.59). For CQ, the percentage of responsive cells was also reduced (C; WT and NaV1.9–/– n ≥ 800 cells, P = 0.038), but the magnitude of the response was similar in WT and NaV1.9–/– DRGs (D; WT and NaV1.9–/– n ≥ 800 cells, P = 0.44). For BAM8-22, no differences were observed for either the percentage of responsive cells (E; WT and NaV1.9–/– n ≥ 800 cells, P = 0.51) or the magnitude of the response (F; WT and NaV1.9–/– n ≥ 800 cells, P = 0.099). *P < 0.05, **P < 0.01, by 2-tailed, unpaired Student’s t test for all data represented as mean ± SEM.