TASK-3–expressing sensory neurons mediate acute and chronic itch via enhancing dorsal horn gastrin-releasing peptide neurons activity

Although canonical itch receptors such as histamine receptor 1 (H1R) and MrgprA3 are well established, they do not fully account for pruritogen-evoked responses, suggesting additional mechanisms regulate pruriceptor excitability. Here, we identify a 2-pore-domain K⁺ channel, the tandem of P domains in a weak inwardly rectifying K⁺ channel–related acid-sensitive K⁺ channel 3 (TASK-3), as a critical modulator of itch. Pharmacological activation of TASK-3 alleviates acute and chronic itch in mice, whereas its inhibition or sensory neuron–specific deletion in dorsal root ganglia (DRG) enhances scratching. We further show that chloroquine and histamine increase the excitability of a subset of sensory neurons by directly inhibiting TASK-3–mediated K⁺ currents. TASK-3–expressing DRG neurons in both mice and humans express the itch-associated neuropeptide neuromedin B (NMB). Notably, this subset of TASK-3⁺/NMB⁺ neurons does not coexpress key canonical itch receptors such as MrgprA3, MrgprD, or H1R. Conditional deletion of TASK-3 in NMB⁺ neurons enhances pruritogen-induced scratching and activates gastrin-releasing peptide (GRP⁺) neurons in the spinal dorsal horn. In chronic itch, TASK-3 expression is downregulated, and its activation suppresses GRP⁺ neuron hyperactivity, whereas TASK-3 knockdown increases excitatory input to these neurons. These findings identify TASK-3 as a pruritogen-sensitive ion channel and a promising therapeutic target for itch relief.