Exploring Biased Agonism at FPR1 as a Means to Encode Danger Sensing

Abstract

Ligand-based selectivity in signal transduction (biased signaling) is an emerging field of G protein-coupled receptor (GPCR) research and might allow the development of drugs with targeted activation profiles. Human formyl peptide receptor 1 (FPR1) is a GPCR that detects potentially hazardous states characterized by the appearance of N-formylated peptides that originate from either bacteria or mitochondria during tissue destruction; however, the receptor also responds to several non-formylated agonists from various sources. We hypothesized that an additional layer of FPR signaling is encoded by biased agonism, thus allowing the discrimination of the source of threat. We resorted to the comparative analysis of FPR1 agonist-evoked responses across three prototypical GPCR signaling pathways, i.e., the inhibition of cAMP formation, receptor internalization, and ERK activation, and analyzed cellular responses elicited by several bacteria-and mitochondria-derived ligands. We also included the anti-inflammatory annexinA1 peptide Ac2-26 and two synthetic ligands, the W-peptide and the small molecule FPRA14. Compared to the endogenous agonists, the bacterial agonists displayed significantly higher potencies and efficacies. Selective pathway activation was not observed, as both groups were similarly biased towards the inhibition of cAMP formation. The general agonist bias in FPR1 signaling suggests a source-independent pathway selectivity for transmission of pro-inflammatory danger signaling.Cells 2020, 9, 1054 2 of 18 translation. However, mitochondria, which are considered to represent endosymbionts of bacterial origin [3], initiate protein biosynthesis with N-formylated methionine and might release detectable levels of formylated peptides in situations of enhanced cell death or trauma [4,5]. Therefore, the appearance of N-formylated peptides signals potentially hazardous states caused by either bacterial threats (PAMPs) or tissue destruction (DAMPs).In higher eukaryotes, this unique pattern is sensed by the family of formyl peptide receptors (FPRs), which belong to the superfamily of G protein-coupled receptors (GPCRs) [5,6]. Thus, a shared sensor system detects bacteria-derived ligands and those that are liberated by non-infectious tissue destruction from mitochondria. The corresponding formylated peptides elicit strong signals via the activation of formyl peptide receptor 1 (FPR1) [7,8]. Here, we addressed whether human FPR1 is capable to decode the actual source of threat via different, i.e., ligand-specific signaling, and consequently modify the elicited cellular responses. We hypothesized that these layers of signal information are encoded by distinguishing ligand perception and potentially are governed by biased agonism. This emerging concept in GPCR-mediated signal transduction [9] emphasizes that ligands selectively stabilize specific receptor conformations that ultimately favor one (or more) signaling pathways out of the many the receptor is linked to. The final cellular response elicited by the receptor/ligand...

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2 complex

“…Our finding that the ability of FPR1 agonists to trigger neutrophil migration is linked to the ability to recruit -arrestin is in agreement with the emerging concept of biased FPR agonism and functional selectivity shown to be valid also for FPR2. [29][30][31]45,68,69 Our data are also in line with the documented role of -arrestin in regulating cell migration in studies performed with other cell types, including neutrophillike HL60 cells. [70][71][72][73] At the structural level, these data suggest that is not reduced by a G q inhibitor, and this is in line with earlier studies that have identified the part of a G i containing G protein downstream of FPR1, to be the link between the receptor an activation of the PLC-PIP 2 -IP 3 -Ca 2+ pathway.…”

“…30,31,79 FPR1 internalization has, however, also been sug-gested to be a G i-independent process. 68 but prime the PAF response. When it comes to the crosstalk between FPR1 and FFAR2, low concentrations of RE-04-001 could be primed by allosterically modulated FFAR2.…”

Annexin Animal Models—From Fundamental Principles to Translational Research

“…Complementing earlier in vivo studies administering recombinant AnxA1 [ 23 , 25 ], Anxa1 −/− mice displayed a boosted immune response characterized by an increased leucocyte migratory behaviour and a substantial resistance to the anti-inflammatory action of glucocorticoids in several acute inflammation models [ 24 ]. Mechanistically, in carrageenan-induced paw oedema and zymosan-induced peritonitis, the prominent ability of AnxA1 to counteract inflammatory events occured through binding of extracellular AnxA1 to formyl peptide receptors (FPRs), a family of G-protein coupled receptors found on many cells of the innate immune system, including neutrophils and monocytes [ 26 , 27 ]. The AnxA1/FPR2 axis inhibits neutrophil recruitment to sites of inflammation, a critical step in the regulation of inflammation [ 28 ].…”

20 Years an Orphan: Is GPR84 a Plausible Medium-Chain Fatty Acid-Sensing Receptor?

“…The cannabinoid receptors respond to both the exogenous phytocannabinoid D 9 -tetrahydrocannabinol as well as half a dozen en-docannabinoids (Felder and Glass, 1998;McPartland et al, 2006). Likewise, FPR1 is a proinflammatory danger-sensing GPCR that not only responds to pathogen-associated molecular patterns of foreign microbial and endogenous mitochondrial origin but also mediates anti-inflammatory effects when activated by the endogenous annexin A1 peptide Ac-2-26 (Gröper et al, 2020).…”