The Atypical Chemerin Receptor GPR1 Displays Different Modes of Interaction with β-Arrestins in Humans and Mice with Important Consequences on Subcellular Localization and Trafficking

Abstract

Atypical chemokine receptors (ACKRs) have emerged as a subfamily of chemokine receptors regulating the local bioavailability of their ligands through scavenging, concentration, or transport. The biological roles of ACKRs in human physiology and diseases are often studied by using transgenic mouse models. However, it is unknown whether mouse and human ACKRs share the same properties. In this study, we compared the properties of the human and mouse atypical chemerin receptor GPR1 and showed that they behave differently regarding their interaction with β-arrestins. Human hGPR1 interacts with β-arrestins as a result of chemerin stimulation, whereas its mouse orthologue mGPR1 displays a strong constitutive interaction with β-arrestins in basal conditions. The constitutive interaction of mGPR1 with β-arrestins is accompanied by a redistribution of the receptor from the plasma membrane to early and recycling endosomes. In addition, β-arrestins appear mandatory for the chemerin-induced internalization of mGPR1, whereas they are dispensable for the trafficking of hGPR1. However, mGPR1 scavenges chemerin and activates MAP kinases ERK1/2 similarly to hGPR1. Finally, we showed that the constitutive interaction of mGPR1 with β-arrestins required different structural constituents, including the receptor C-terminus and arginine 3.50 in the second intracellular loop. Altogether, our results show that sequence variations within cytosolic regions of GPR1 orthologues influence their ability to interact with β-arrestins, with important consequences on GPR1 subcellular distribution and trafficking.

Cryo-EM structures of the human G-protein coupled receptor 1 (GPR1) – Gi protein complexes bound to the full-length chemerin and to its C-terminal nonapeptide

“…The same also applied to the C9 peptide, that showed a higher potency (EC 50 of 1 nM) on GPR1 than on CMKLR1 (24 nM). Based on these results, GPR1 was considered a receptor that preferentially activates the β-arrestin2 pathway (Barnea et al, 2008; Fischer et al, 2021), although other studies showed its ability to mediated G protein signaling as well (De Henau et al, 2016; Degroot et al, 2022).…”

Understanding the Role of Chemerin in the Pathophysiology of Pre-Eclampsia

“…The binding of chemerin to GPR1 results in a weak Ca2+ mobilization and phosphorylation of ERK1/2, but this action participates in the anti-inflammatory response, development of adiposity, hormone secretion, and the regulation of glucose balance in obesity, as well as in the regulation of angiogenesis [ 21 , 22 ]. Both CMKLR1 and GPR1 activation can lead to the recruitment of β-arrestins and receptor internalization [ 23 , 24 ]. GPR1 serves additionally as a scavenger receptor for peptides that cannot stimulate receptor activation.…”

“…GPR1 serves additionally as a scavenger receptor for peptides that cannot stimulate receptor activation. Interestingly, GPR1 is not expressed in monocytes, macrophages, or peripheral blood lymphocytes, but instead, it is expressed in cells related to the central nervous system [ 24 , 25 ]. Although chemerin is the only identified ligand for CCRL2, its interaction does not initiate any known signaling pathway; thus, its role remains uncertain; however, it seems to have the ability to amplify local chemerin concentration for CMKLR1 interaction [ 19 , 26 ].…”

Chemerin: A Functional Adipokine in Reproductive Health and Diseases

“…Unlike CMKLR1, the binding of chemerin to GPR1 results in a weak Ca 2+ mobilization and phosphorylation of ERK1/2, and the binding of chemerin to CCRL2 does not signal nor internalize [ 31 ]. Recent findings reported that GPR1 displayed rapid ligand-independent, constitutive internalization and acted as a scavenging receptor with wider ligand specificity [ 34 , 35 ]. These results indicate that CMKLR1 is a typical GPCR for chemerin with canonical G protein-related signaling features, while GPR1 and CCRL2 are atypical GPCRs ( Figure 1 B), and more detailed properties of these receptors are needed for further work.…”