Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 128, Issue 12, Pages 5434-5447Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI122481
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Funding
- Department of Defense National Defense Science and Engineering Graduate Fellowship
- Blaustein Pain Research grant
- Johns Hopkins Catalyst Award
- Johns Hopkins Bridge Funding Award
- NIH [R01DE022750, R01NS054791]
- Hugo W. Moser Research Institute at Kennedy Krieger Inc.
- [T32 GM007445]
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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(V)1.9, a voltage-gated sodium (Na-V) channel subtype that relays sensory information from the periphery to the spine. To investigate the role of Na(V)1.9 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(V)1.9-expressing neurons. We also assessed Na(V)1.9 involvement in itch by using a newly created Na(V)1.9(-/-) and Na(V)1.9(L799P/WT) mouse model. We found that Na(V)1.9 is expressed in a subset of nonmyelinated, nonpeptidergic small-diameter dorsal root ganglia (DRGs). In WT DRGs, but not those of Na(V)1.9(-/-) mice, pruritogens altered action potential parameters and Na-V channel gating properties. Additionally, Na(V)1.9(-/-) mice exhibited a strong reduction in acute scratching behavior in response to pruritogens, whereas Na(V)1.9(L799P/WT) mice displayed increased spontaneous scratching. Altogether, our data suggest an important contribution of Na(V)1.9 to itch signaling.
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