Anoctamin 1/TMEM16A in pruritoceptors is essential for Mas-related G protein receptor-dependent itch

Kim, Hyesu^1,3,7; Kim, Hyungsup^1,7; Cho, Hawon²; Lee, Byeongjun¹; Lu, Huan-Jun¹; Kim, Kyungmin¹; Chung, Sooyoung¹; Shim, Won-Sik⁴; Shin, Young Kee³; Dong, Xinzhong⁵; Wood, John N⁶; Oh, Uhtaek^1,3,*Author InformationPAIN: February 08, 2022 – Volume – Issue –doi: 10.1097/j.pain.0000000000002611

Abstract

Itch is an unpleasant sensation that evokes a desire to scratch. Pathologic conditions such as allergy or atopic dermatitis produce severe itching sensation. Mas-related G protein receptors (Mrgprs) are receptors for many endogenous pruritogens. However, signaling pathways downstream to these receptors in dorsal root ganglion (DRG) neurons are not yet understood. We found that Anoctamin 1 (ANO1), a Ca²⁺-activated chloride channel, is a transduction channel mediating Mrgprs-dependent itch signals. Genetic ablation of Ano1 in DRG neurons displayed a significant reduction in scratching behaviors in response to acute and chronic Mrgprs-dependent itch models and the epidermal hyperplasia induced by dry skin. In-vivo Ca²⁺ imaging and electrophysiological recording revealed that chloroquine and other agonists of Mrgpr receptors excited DRG neurons via ANO1. More importantly, the overexpression of Ano1 in DRG neurons of Ano1-deficient mice rescued the impaired itching observed in Ano1-deficient mice. These results demonstrate that ANO1 mediates the Mrgprs-dependent itch signaling in pruriceptors and provides clues to treating pathologic itch syndromes.