TRESK BACKGROUND POTASSIUM CHANNEL REGULATES MRGPRA3<SUP>+</SUP> PRURICEPTOR EXCITABILITY AND ITCH SENSITIVITY

A subset of sensory neurons expressing specific Mas-related G protein-coupled receptors (Mrgprs) and TRP channels mediates pruritogen-induced chemical itch, yet the mechanisms controlling their excitability remain unclear. TRESK is a background K⁺ channel expressed in these neurons that regulates resting membrane potential, action potential firing and neuronal excitability, and it has been involved in somatosensation and pain transduction. Here, we show that TRESK contributes to itch sensitivity and represents a potential target for the treatment of chronic pruritus. Combining RNA in situ hybridization, calcium imaging, electrophysiological, and behavioral assays, we found that TRESK is involved in the modulation of non-histaminergic itch. In situ hybridization experiments show that TRESK is co-expressed with MrgprA3 and MrgprD in mouse sensory neurons, and with MrgprX1 in human ones. Genetic ablation of TRESK increases firing of MrgprA3-expressing pruriceptors and acute itch in response to chloroquine, while the response to histamine, BAM8-22, or LTC4 is unaffected. TRESK knockout mice also produced exacerbated scratching in mice models producing chronic itch as allergic contact dermatitis, dry skin, and psoriasis. Moreover, pharmacological enhancing of TRESK reduces both acute and chronic itch in WT mice but not in TRESK KO animals. In summary, our data indicates that TRESK plays a role in controlling the excitability of MrgprA3⁺ sensory neurons that mediate histaminergic-independent itch. Enhancing the channel function with specific activators constitute a novel anti-pruritic therapeutic method that can be combined with other compounds for the treatment of non-histaminergic acute and chronic itch, for which appropriate treatments are lacking.