2 research outputs found
Ligand-binding and -scavenging of the chemerin receptor GPR1
Tight regulation of cytokines is essential for the initiation and resolution of inflammation. Chemerin, a mediator of innate immunity, mainly acts on chemokine-like receptor 1 (CMKLR1) to induce the migration of macrophages and dendritic cells. The role of the second chemerin receptor, G protein-coupled receptor 1 (GPR1), is still unclear. Here we demonstrate that GPR1 shows ligand-induced arrestin3 recruitment and internalization. The chemerin C-terminus triggers this activation by folding into a loop structure, binding to aromatic residues in the extracellular loops of GPR1. While this overall binding mode is shared between GPR1 and CMKLR1, differences in their respective extracellular loop 2 allowed for the design of the first GPR1-selective peptide. However, our results suggest that ligand-induced arrestin recruitment is not the only mode of action of GPR1. This receptor also displays constitutive internalization, which allows GPR1 to internalize inactive peptides efficiently by an activation-independent pathway. Our results demonstrate that GPR1 takes a dual role in regulating chemerin activity: as a signaling receptor for arrestin-based signaling on one hand, and as a scavenging receptor with broader ligand specificity on the other.
Graphic abstractDeutsche Forschungsgemeinschaft
http://dx.doi.org/10.13039/501100001659Universität Leipzig (1039)Peer Reviewe
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International Union of Basic and Clinical Pharmacology: Chemerin Receptors CMKLR1 (ChemerinWell1) and GPR1 (Chemerin2) Nomenclature, Pharmacology and Function
Chemerin, a chemoattractant protein and adipokine, has been identified as the endogenous ligand for a G protein-coupled receptor encoded by the gene CMKLR1 (also known as ChemR23) and as a consequence the receptor protein was renamed the chemerin receptor in 2013. Since then, chemerin has been identified as the endogenous ligand for a second G protein-coupled receptor, encoded by the gene GPR1. Therefore, the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification recommends that the official name of the receptor protein for CMKLR1 is chemerin receptor 1 and GPR1 is chemerin receptor 2 to follow the convention of naming the receptor protein after the endogenous ligand. Chemerin receptor 1 and chemerin receptor 2 can be abbreviated to Chemerin1 and Chemerin2 respectively. Chemerin requires C-terminal processing for activity and human chemerin21-157 is reported to be the most active form, with peptide fragments derived from the C-terminus biologically active at both receptors. Small molecule antagonist, CCX832, selectively blocks CMKLR1, and resolvin E1 activation of CMKLR1 is discussed. Activation of both receptors by chemerin is via coupling to Gi/o causing inhibition of adenylyl cyclase and increased Ca2+ flux. Receptors and ligand are widely expressed in human, rat and mouse, and both receptors share ~80% identity across these species. CMKLR1 knock-out mice highlight the role of this receptor in inflammation and obesity and similarly GPR1 knock-out mice exhibit glucose intolerance. In addition, the chemerin receptors have been implicated in cardiovascular disease, cancer, steroidogenesis, HIV replication and neurogenerative disease