Characterization of GPR182 as a scavenging atypical chemokine receptor

While G protein coupled receptor (GPCR) are one of the largest family of receptors, only 40% of the entire GPCR-ome has been targeted with therapeutic drugs. Efforts to characterize the pharmacology, anatomical locations, and physiological functions of the orphan GPCRs are crucial to the development of new drugs to benefit human health. G protein–coupled receptor 182 (GPR182, also known as adrenomedullin receptor), is a class A orphan GPCR. GPR182’s closest paralog, with only ~30% sequence homology, is the atypical chemokine receptor 3 (ACKR3). The ACKRs comprise a subfamily of rhodopsin like G-protein coupled receptors with unique binding abilities for a variety of chemokine ligands. Currently four members of the subfamily, ACKR1-4, have been identified and characterized. The molecular mechanisms whereby ACKRs perform their scavenging function are an area of intense research. The conventional wisdom is that upon ligand binding, ACKRs internalize into endosomes, where the ligand is degraded and the receptor recycled to the cell membrane.

Work from a team of leading chemokine experts in Frontiers in Immunology used recombinant fluorescently labeled chemokines and other state of the art approaches to demonstrate that GPR182 binds several chemokine ligands without invoking canonical chemokine receptor signaling. These data are consistent with GPR182 working as a chemokine scavenger. They also established the mechanisms for internalization and indicate that unlike other ACKRs, GPR182 requires beta-arrestin for its internalization. Its expression is predominantly localized to endothelial cells. GRP182 knockout mice have decreased secondary lymphoid tissues and smaller marginal zones, with diminished T-independent humoral immune responses. On the basis of these efforts, a subsequent report in Pharmacological Reviews designates GPR182 as the fifth atypical chemokine receptor ACKR5.

Protein Foundry routinely engineers fluorescently labeled chemokine ligands like those shown in Melgrati to bind chemokine and atypical chemokine receptors with full biological activity.