Migration mediated by the oxysterol receptor GPR183 depends on arrestin coupling but not receptor internalization

The chemotactic G protein-coupled receptor GPR183 and its most potent endogenous oxysterol ligand 7 alpha,25dihydroxycholesterol (7 alpha,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. beta-arrestin potentiated ligandinduced 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 beta-arrestin-independent manner, suggesting the existence of different pools of surface-localized GPR183. Chemotaxis mediated by GPR183 depended on receptor desensitization by beta-arrestins but could be uncoupled from internalization, highlighting an important biological role for the recruitment of beta-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.

Automated summary

The chemotactic receptor GPR183 and its ligand 7 alpha,25-OHC play important roles in immune cell positioning. The internalization of GPR183 is influenced by the C terminus, β-arrestin, caveolin, and dynamin. β-arrestin enhances ligand-induced internalization of GPR183, but it is not required. Internalization and chemotaxis are regulated by distinct mechanisms involving G protein activation and β-arrestin-mediated desensitization. These findings have implications for the development of GPR183-targeting drugs for specific diseases.