LAUSR

The chemotactic G protein–coupled receptor GPR183 and its most potent endogenous oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-OHC) are important for immune cell positioning in secondary lymphoid tissues. This receptor-ligand pair is associated with various diseases, in some cases contributing favorably and in other cases adversely, making GPR183 an attractive target for therapeutic intervention. We investigated the mechanisms underlying GPR183 internalization and the role of internalization in the main biological function of the receptor, chemotaxis. We found that the C terminus of the receptor was important for ligand-induced internalization but less so for constitutive (ligand-independent) internalization. β-arrestin potentiated ligand-induced internalization but was not required for ligand-induced or constitutive internalization. Caveolin and dynamin were the main mediators of both constitutive and ligand-induced receptor internalization in a mechanism independent of G protein activation. Clathrin-mediated endocytosis also contributed to constitutive GPR183 internalization in a β-arrestin–independent manner, suggesting the existence of different pools of surface-localized GPR183. Chemotaxis mediated by GPR183 depended on receptor desensitization by β-arrestins but could be uncoupled from internalization, highlighting an important biological role for the recruitment of β-arrestin to GPR183. The role of distinct pathways in internalization and chemotaxis may aid in the development of GPR183-targeting drugs for specific disease contexts. Description The interaction of the GPCR GPR183 with β-arrestins rather than receptor internalization drives chemotactic function. Arresting interactions for chemotaxis GPR183 is a GPCR for oxysterol ligands, including 7α,25-OHC, and mediates the migration of various immune cells and their proper positioning in lymphoid tissues. In addition to its involvement in physio-logical processes, such as insulin secretion and antibody responses, GPR183 is also associated with cancers and neurodegenerative and inflammatory diseases, making it an important therapeutic target. Kjær et al. characterized the signaling and regulation of GPR183 function in cells in response to various ligands. Unlike many other chemotactic GPCRs, GPR183 internalization was β-arrestin–independent. Moreover, GPR183 interacted with caveolae rather than clathrin for ligand-induced internalization and required β-arrestin for 7α;,25-OHC–dependent chemotaxis. Together, these findings will aid in develop-ing ligands that can target specific effects of GPR183 activity in different settings. --JFF