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

Abstract

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.