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 2

sfGFP-NaV1.9 expression patterns.

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sfGFP-NaV1.9 expression patterns. (A–H) DRG sections from sfGFP-NaV1.9 m...
(A–H) DRG sections from sfGFP-NaV1.9 mice stained for the indicated markers. TH, tyrosine hydroxylase. (I) Graph of cell area in DRGs with the total number of neurons by cell size (black bars), using the pan-neuronal marker PGP9.5, as well as the neurons positive for GFP staining (gray bars, n ≥ 200 GFP+ neurons and n ≥ 600 PGP9.5+). (J) Graph showing the fraction of neurons positive for the markers indicated that were also positive for GFP (n ≥ 200 neurons). (K–M) Sections of the dorsal horn stained with GFP and IB4 (K), the saphenous nerve stained with GFP and PGP9.5 (L), and glabrous skin of the hind paw stained with GFP and PGP9.5 (M). Panels to the right of each image (K–M) show enlarged pictures of the corresponding section in the white box. Scale bars: 50 μm.