Signaling Properties of Chemerin Receptors CMKLR1, GPR1 and CCRL2

Abstract

Chemerin is a small chemotactic protein originally identified as the natural ligand of CMKLR1. More recently, two other receptors, GPR1 and CCRL2, have been reported to bind chemerin but their functional relevance remains poorly understood. In this study, we compared the binding and signaling properties of the three human chemerin receptors and showed differences in mode of chemerin binding and receptor signaling. Chemerin binds to all three receptors with low nanomolar affinities. However, the contribution of the chemerin C-terminus to binding efficiency varies greatly amongst receptors. By using BRET-based biosensors monitoring the activation of various G proteins, we showed that binding of chemerin and the chemerin 9 nonapeptide (149YFPGQFAFS157) to CMKLR1 activates the three Gαi subtypes (Gαi1, Gαi2 and Gαi3) and the two Gαo isoforms (Gαoa and Gαob) with potencies correlated to binding affinities. In contrast, no significant activation of G proteins was detected upon binding of chemerin to GPR1 or CCRL2. Binding of chemerin and the chemerin 9 peptide also induced the recruitment of β-arrestin1 and 2 to CMKLR1 and GPR1, though to various degree, but not to CCRL2. However, the propensity of chemerin 9 to activate β-arrestins relative to chemerin is higher when bound to GPR1. Finally, we showed that binding of chemerin to CMKLR1 and GPR1 promotes also the internalization of the two receptors and the phosphorylation of ERK1/2 MAP kinases, although with a different efficiency, and that phosphorylation of ERK1/2 requires both Gαi/o and β-arrestin2 activation but not β-arrestin1. Collectively, these data support a model in which each chemerin receptor displays selective signaling properties.

Chemerin-induced arterial contraction is Gi- and calcium-dependent

“…3A and B) point to the chemerin receptor being G i -coupled and the primary functional receptor in these cells. Additionally, there is recent data suggesting that the receptor GPR1 does not significantly activate G-proteins and may act like a decoy receptor [30]. This is consistent with our data and further solidifies the chemerin receptor’s role as the principle receptor for chemerin in vascular smooth muscle cells.…”

“…A recent report also noted that the binding of chemerin-9 to the chemerin receptor activated Erk MAPK [30]. Beyond this, Erk MAPK is extensively associated with the actions of chemerin in chemotaxis [19], angiogenesis [58], and adipogenesis [10].…”

Chemokine (C-C Motif) Receptor-Like 2 is not essential for lung injury, lung inflammation, or airway hyperresponsiveness induced by acute exposure to ozone

“…), and in support of the classification of Ccrl2 as an atypical chemokine receptor, chemerin does not activate G protein signaling when binding Ccrl2 (De Henau et al. ). In addition to Ccrl2, chemerin is a ligand for chemokine‐like receptor 1 (Cmklr1) and G protein‐coupled receptor 1 (Gpr1) (Bondue et al.…”

“…), Ccrl2 is incapable of activating G proteins (De Henau et al. ), yet Ccrl2 has the ability to facilitate leukocyte chemotaxis (Zabel et al. ; Otero et al.…”

“…Chemokine (C-C motif) receptor-like 2 (Ccrl2) is a member of this family and is expressed by a variety of cells, including astrocytes, B lymphocytes, dendritic cells, endothelial cells, macrophages, mast cells, microglia, and neutrophils (Shimada et al 1998;Brouwer et al 2004;Galligan et al 2004;Oostendorp et al 2004;Hartmann et al 2008;Zabel et al 2008;Otero et al 2010;Monnier et al 2012;Bachelerie et al 2014;Del Prete et al 2017;Monaghan 2017). While the majority of receptors within the chemokine receptor family initiate leukocyte trafficking via G protein-dependent signaling (Bachelerie et al 2014), Ccrl2 is incapable of activating G proteins (De Henau et al 2016), yet Ccrl2 has the ability to facilitate leukocyte chemotaxis (Zabel et al 2008;Otero et al 2010;Monnier et al 2012;Del Prete et al 2017). Because Ccrl2 influences leukocyte migration in the absence of G protein signaling, Ccrl2 is subclassified as an atypical chemokine receptor within the chemokine receptor family (Bachelerie et al 2014).…”