Selective phosphorylation of threonine residues defines GPR84-arrestin interactions of biased ligands.

ABSTRACT: GPR84 is an immune cell-expressed, proinflammatory receptor currently being assessed as a therapeutic target in conditions including fibrosis and inflammatory bowel disease. Although it was previously shown that the orthosteric GPR84 activators 2-HTP and 6-OAU promoted its interactions with arrestin-3, a G protein-biased agonist DL-175 did not. Here, we show that replacement of all 21 serine and threonine residues within i-loop 3 of GPR84, but not the two serines in the C-terminal tail, eliminated the incorporation of [³²P] and greatly reduced receptor-arrestin-3 interactions promoted by 2-HTP. GPR84 was phosphorylated constitutively on residues Ser²²¹ and Ser²²⁴, while various other amino acids are phosphorylated in response to 2-HTP. Consistent with this,

SUBMITTER: Marsango S 

PROVIDER: S-EPMC9118924 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature