Biased perspectives on formyl peptide receptors

Raabe, Carsten A.; Gröper, Jieny; Rescher, Ursula

doi:10.1016/j.bbamcr.2018.11.015

Cited by 56 publications

(49 citation statements)

References 147 publications

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“…FPR1 and the corresponding large repertoire of FPR1 agonists, derived from various cellular and pathogenic sources, constitute a powerful system for the detection of insults that are linked with tissue destruction under infectious and sterile conditions, such as pathogenic challenges or trauma caused by burns or injury [9,45]. Because overactivation of the innate immune response is often correlated with excessive and deleterious tissue damage, e.g., in influenza A virus (IAV) infection, targeting the FPR family might represent a novel approach to balance innate immunity.…”

Section: Discussionmentioning

confidence: 99%

“…Generally, the often observed signaling diversity elicited by GPCR agonists that are acting on the same receptor is based on the ligand preference for certain receptor conformational states linked to a subset of all possible signaling responses. This diversity has been termed "functional selectivity" and has led to the concept of "biased agonism" and helps to explain different regulatory outcomes via the activation of the same receptor [9,11]. Therapeutically, bias analysis might help to identify compounds that direct receptor signaling toward desired responses, thus aiding in the development of novel therapeutics with an effective pharmacological profile that avoids activation of unwanted signaling pathways and hence side effects [48,49].…”

Section: Discussionmentioning

confidence: 99%

“…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 interaction is therefore biased towards specific signaling pathways [9][10][11]. We also considered that the different classes of agonists might group due to their efficacies and potencies for the same cellular pathways, i.e., apart from the selective activation of entirely different signaling pathways.…”

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confidence: 99%

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

Gröper

König

Kostenis

et al. 2020

Cells

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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...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Gröper

König

Kostenis

et al. 2020

Cells

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“…FPR2 is also referred as FPR2/ALX, in which ALX means the receptor for LXA 4 1,14 . While most peptide ligands such as formylpeptides act on FPR2 to induce chemotaxis of immune cells and initiate numerous inflammatory processes, FPR2 signaling by SPMs promotes the resolution of inflammation 2,3,15 . A host-derived lipid-binding protein involved in the anti-inflammatory action of glucocorticoids, annexin A1, and its derived peptides, can also act on FPR2 as pro-resolving or anti-inflammatory agents 16 .…”

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confidence: 99%

Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling

et al. 2020

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Formylpeptide receptors (FPRs) as G protein-coupled receptors (GPCRs) can recognize formylpeptides derived from pathogens or host cells to function in host defense and cell clearance. In addition, FPRs, especially FPR2, can also recognize other ligands with a large chemical diversity generated at different stages of inflammation to either promote or resolve inflammation in order to maintain a balanced inflammatory response. The mechanism underlying promiscuous ligand recognition and activation of FPRs is not clear. Here we report a cryo-EM structure of FPR2-G i signaling complex with a peptide agonist. The structure reveals a widely open extracellular region with an amphiphilic environment for ligand binding. Together with computational docking and simulation, the structure suggests a molecular basis for the recognition of formylpeptides and a potential mechanism of receptor activation, and reveals conserved and divergent features in G i coupling. Our results provide a basis for understanding the molecular mechanism of the functional promiscuity of FPRs.

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“…FPR2/Fpr2 is able to respond to both bacterial and endogenously released formylated peptides, to exert both pro-and antiinflammatory actions [40]. In addition, recent data show that some ligands trigger biased signaling and induce selective functional responses [41,42]. Several FPR agonists promote inflammation resolution in in vivo disease models [43].…”

Section: Discussionmentioning

confidence: 99%

Formyl peptide receptor 2 orchestrates mucosal protection againstCitrobacter rodentiuminfection

et al. 2019

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Citrobacter rodentium is an attaching and effacing intestinal murine pathogen which shares similar virulence strategies with the human pathogens enteropathogenic-and enterohemorrhagic Escherichia coli to infect their host. C. rodentium is spontaneously cleared by healthy wild-type (WT) mice whereas mice lacking Muc2 or specific immune regulatory genes demonstrate an impaired ability to combat the pathogen. Here we demonstrate that apical formyl peptide receptor 2 (Fpr2) expression increases in colonic epithelial cells during C. rodentium infection. Using a conventional inoculum dose of C. rodentium, both WT and Fpr2 −/− mice were infected and displayed similar signs of disease, although Fpr2 −/− mice recovered more slowly than WT mice. However, Fpr2 −/− mice exhibited increased susceptibility to C. rodentium colonization in response to low dose infection: 100% of the Fpr2 −/− and 30% of the WT mice became colonized and Fpr2 −/− mice developed more severe colitis and more C. rodentium were in contact with the colonic epithelial cells. In line with the larger amount of C. rodentium detected in the spleen in Fpr2 −/− mice, more C. rodentium and enteropathogenic Escherichia coli translocated across an in vitro mucosal surface to the basolateral compartment following FPR2 inhibitor treatment. Fpr2 −/− mice also lacked the striated inner mucus layer that was present in WT mice. Fpr2 −/− mice had decreased mucus production and different mucin O-glycosylation in the colon compared to WT mice, which may contribute to their defect inner mucus layer. Thus, Fpr2 contributes to protection against infection and influence mucus production, secretion and organization.

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Biased perspectives on formyl peptide receptors

Cited by 56 publications

References 147 publications

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

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

Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling

Formyl peptide receptor 2 orchestrates mucosal protection againstCitrobacter rodentiuminfection

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