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 5

APs are influenced by NaV1.9 and CQ.

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APs are influenced by NaV1.9 and CQ. (A) Representative APs for WT (blue...
(A) Representative APs for WT (blue), NaV1.9–/– (green), WT in the presence of CQ (100 μM, red), and NaV1.9–/– mice in the presence of CQ (100 μM, purple). Dotted lines represent the resting membrane potential (RMP) for WT and NaV1.9–/–: –40.0 ± 1.3 mV and –31.5 ± 2.7 mV, respectively (n = 13 for WT and n = 12 for NaV1.9–/–; **P = 0.009). (B) Quantification of AP parameters in WT and NaV1.9–/– DRGs. Amplitude of AP (WT n = 16 and NaV1.9–/– n = 20, P = 0.44) and threshold to elicit an AP were not affected (WT n = 20 and NaV1.9–/– n = 20, P = 0.67). NaV1.9–/– APs had a slower time to peak (T to peak; WT n = 17 and NaV1.9–/– n = 20, P = 0.016) and a faster time to minimum (T to min; WT n = 21 and NaV1.9–/– n = 18, P = 0.004). (C) CQ treatment affects the AP amplitude and threshold but not kinetics. Amplitude of AP (WT n = 16 and with CQ n = 16, P = 0.002) and threshold to elicit an AP (WT n = 20 and with CQ n = 16, P = 0.033) were significantly lower. T to peak (WT n = 17 and with CQ n = 17, P = 0.063) and T to min (WT n = 21 and with CQ n = 18, P = 0.732) were not significantly different. (D) These effects do not occur in NaV1.9–/– DRGs: AP (NaV1.9–/– n = 20 and with CQ n = 12, P = 0.5), the threshold to elicit an AP (NaV1.9–/– n = 20 and with CQ n = 12, P = 0.855), T to peak (NaV1.9–/– n = 20 and with CQ n = 12, P = 0.219), and T to min (NaV1.9–/– n = 18 and with CQ n = 16, P = 0.157) were not statistically significant. *P < 0.05, **P < 0.01, by 2-tailed, unpaired Student’s t test was used for RMP, and Mann-Whitney was used for all other data comparisons, which are represented as mean ± SEM. See Table 1 for values.