Sphingosylphosphorylcholine induces itch via activation of TRPM3 and TRPA1 in mice.

Itch is a prevalent symptom in atopic dermatitis (AD), often leading to a strong urge to scratch. Elevated levels of sphingosylphosphorylcholine (SPC) are found in the stratum corneum of AD patients, and while SPC is known to induce itch, its molecular targets are not well understood. This study aims to identify the signaling pathway of SPC-induced itch under AD conditions. We demonstrate that SPC specifically activates the Transient Receptor Potential Melastatin 3 (TRPM3) channel in sensory neurons. In HEK293T cells expressing TRPM3, SPC treatment caused a significant increase in intracellular calcium, which was inhibited by TRPM3 antagonists. Among various TRP channels tested, TRPM3 exhibited the highest reactivity to SPC, followed by TRPA1. Molecular docking analysis also supported interactions between SPC and both TRPM3 and TRPA1. In an AD mouse model, SPC-induced responses were dependent on TRPM3 and TRPA1, and the expression of these channels increased in dorsal root ganglion neurons. SPC-induced scratching behaviors were significantly reduced by TRPM3 and TRPA1 antagonists, with TRPM3 playing a critical role in spontaneous scratching. This study identifies TRPM3 and TRPA1 as key mediators of SPC-induced itch, providing potential therapeutic targets for treating itch in AD patients.