Upregulation of DRG protein TMEM100 facilitates dry skin-induced pruritus by enhancing TRPA1 channel function

The dry skin tortures numerous patients with severe itch. The transient receptor potential cation channel V member 1 (TRPV1) and A member 1 (TRPA1) are two essential receptors for peripheral neural coding of itch sensory, mediating histaminergic and nonhistaminergic itch separately. In the dorsal root ganglion, transmembrane protein 100 (TMEM100) is structurally related to both TRPV1 and TRPA1 receptors, but the exact role of TMEM100 in itch sensory coding is still unknown. Here, in this study, we find that TMEM100+ DRG neurons account for the majority of activated neurons in an acetone-ether-water (AEW)-induced dry skin itch model, and some TMEM100(+) DRG neurons are colocalized with both TRPA1 and the chloroquine-related Mrgpr itch receptor family. Both the expression and function of TRPA1 channels, but not TRPV1 channels, are upregulated in the AEW model, and specific DRGTmem100 gene knockdown alleviates AEW-induced itch and rescues the expression and functional changes of TRPA1. Our results strongly suggest that TMEM100 protein in DRG is the main facilitating factor for dry skin-related chronic itch, and specific suppression of TMEM100 in DRG could be a novel effective treatment strategy for patients who suffer from dry skin-induced itch.