Tmem45b Modulates itch via Endoplasmic Reticulum Calcium Regulation

Chronic itch is detected by dorsal root ganglia (DRG) that severely impairs quality of life. However, its underlying mechanisms remain poorly understood. We identified that Tmem45b was contained in natriuretic peptide type B (Nppb)-, mas-related G-protein coupled receptor member A3 (Mrgpra3)-, and Mrgprd-positive DRG neurons, which are associated with itch sensation. The role of Tmem45b in itch sensation has not been explored. Tmem45b conditional knockout (cKO) mice exhibited decreased scratching to ß-alanine, and increased scratching to chloroquine. Notably, Tmem45b cKO alleviated chronic itch. Furthermore, Tmem45b cKO impaired the calcium response to ß-alanine and allyl isothiocyanate but not to chloroquine in dissociated DRG neurons. Tmem45b deficiency led to significant downregulation of sarco/endoplasmic reticulum calcium transport ATPase 1 (Serca1), impairing calcium storage capacity of endoplasmic reticulum (ER). Inhibition of Serca1 in DRG neurons reduced intracellular calcium release triggered by ß-alanine and chloroquine. Together,Tmem45b deficiency may reduce nonhistaminergic itch and disrupt ER calcium regulation, highlighting a potential target for chronic itch therapy. Overall design: RNA sequencing was performed on the dorsal root ganglia (DRG) tissues of Tmem45b-flox mice, Tmem45b-flox::Mrgprd-cre mice, CFA-induced Tmem45b-flox mice, and CFA-induced Tmem45b-flox::Mrgprd-cre mice to explore gene expression changes under different experimental conditions.