RGS6 is a key regulator of itch in female mice.

Pruritus, commonly known as itch, is a protective somatosensory sensation whose dysregulation is a common feature of many pathologic conditions and can severely impact quality of life. Despite its clinical relevance, itch perception is among the least well known of all somatosensory modalities. G protein coupled receptors (GPCRs) in pruritic circuits are key modulators of itch, however the intracellular regulators of GPCR signaling in itch circuits remain largely unexplored. Regulators of G protein signaling (RGS) proteins are vital modulators of GPCR signaling and may influence itch processing in histaminergic and non-histaminergic circuits. Here we report that RGS6, a member of the R7 RGS protein family, modulates itch through both histaminergic and non-histaminergic mechanisms in female mice. Using global knockout mouse models, we show that this anti-pruritic phenotype is specific to RGS6, with no comparable effect in RGS7, highlighting functional specificity within the R7 RGS family. This study uncovers a regulatory role of RGS6 in modulating pruritus in females and provides critical insights into mechanisms fundamental to acute and pathological itch.