A disease mutation reveals a role for Na_V1.9 in acute itch

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 Na_V1.9, a voltage-gated sodium (Na_V) channel subtype that relays sensory information from the periphery to the spine. To investigate the role of Na_V1.9 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 Na_V1.9-expressing neurons. We also assessed Na_V1.9 involvement in itch by using a newly created Na_V1.9^–/– and Na_V1.9^L799P/WT mouse model. We found that Na_V1.9 is expressed in a subset of nonmyelinated, nonpeptidergic small-diameter dorsal root ganglia (DRGs). In WT DRGs, but not those of Na_V1.9^–/– mice, pruritogens altered action potential parameters and Na_V channel gating properties. Additionally, Na_V1.9^–/– mice exhibited a strong reduction in acute scratching behavior in response to pruritogens, whereas Na_V1.9^L799P/WT mice displayed increased spontaneous scratching. Altogether, our data suggest an important contribution of Na_V1.9 to itch signaling.