Superagonism at G protein‐coupled receptors and beyond

Schrage, R; Min, Anna De; Hochheiser, Katharina; Kostenis, Evi; Mohr, Klaus

doi:10.1111/bph.13278

Cited by 27 publications

(29 citation statements)

References 89 publications

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“…An alternative approach classifies agonist efficacies in relation to an endogenous reference agonist of high efficacy. Therefore, some agonists might be identified, which are even capable to elicit stronger cellular responses than those associated with the reference agonist; consequently, these ligands are referred to as "superagonists", although this term still has to be defined in broader detail [53]. The molecular explanation for this phenomenon might lie in the observation that simultaneous binding of an efficacious agonist and a G protein is required to induce the full receptor response [54,55].…”

Section: Discussionmentioning

confidence: 99%

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%

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

Gröper

König

Kostenis

et al. 2020

Cells

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“…Theorthosteric building block iperoxo,asynthetic agonist for all mAChR subtypes, [20] was used as ar eference for all experiments and showed full agonism (EC 50 = 0.57 mm). Theorthosteric building block iperoxo,asynthetic agonist for all mAChR subtypes, [20] was used as ar eference for all experiments and showed full agonism (EC 50 = 0.57 mm).…”

mentioning

confidence: 99%

A Photoswitchable Dualsteric Ligand Controlling Receptor Efficacy

et al. 2017

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The investigation of the mode and time course of the activation of G-protein-coupled receptors (GPCRs), in particular muscarinic acetylcholine (mACh or M) receptors, is still in its infancy despite the tremendous therapeutic relevance of M receptors and GPCRs in general. We herein made use of a dualsteric ligand that can concomitantly interact with the orthosteric, that is, the neurotransmitter, binding site and an allosteric one. We synthetically incorporated a photoswitchable (photochromic) azobenzene moiety. We characterized the photophysical properties of this ligand called BQCAAI and investigated its applicability as a pharmacological tool compound with a set of FRET techniques at the M receptor. BQCAAI proved to be an unprecedented molecular tool; it is the first photoswitchable dualsteric ligand, and its activity can be regulated by light. We also applied BQCCAI to investigate the time course of several receptor activation processes.

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“…The compounds exhibited low nanomolar potency when inhibiting cAMP and are more efficacious than NMU‐8, with NY0128 eliciting almost twice the effect elicited by NMU‐8. These data suggest they are acting as superagonists because their effects are greater than the effect of the endogenous agonist NMU‐8 at the NMUR2 through the G i/o signaling pathway.…”

Section: Discussionmentioning

confidence: 96%

Small‐Molecule Neuromedin U Receptor 2 Agonists Suppress Food Intake and Decrease Visceral Fat in Animal Models

Sampson

Kasper

Felsing

et al. 2018

Pharmacology Res & Perspec

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Obesity is a growing public health concern, with 37.5% of the adult population in need of therapeutics that are more efficacious with a better side effect profile. An innovative target in this regard is neuromedin U, a neuropeptide shown to suppress food intake and attenuate weight gain in animal models. These effects of neuromedin U on feeding behavior are thought to be related to agonism at the centrally expressed neuromedin U receptor 2 (NMUR2). As peptides present unique challenges that limit their therapeutic potential, the discovery of small‐molecule NMUR2 agonists is needed to validate the targets therapeutic value, but to date, none have been evaluated in any animal model of disease. We therefore assessed two small‐molecule NMUR2 agonists for their in vitro signaling and their in vivo efficacy. The NMUR2 agonists were synthesized and both NMUR2 agonists, NY0116 and NY0128, decreased cAMP while stimulating calcium signaling in stably expressing NMUR2 HEK293 cells. When small‐molecule NMUR2 agonists were tested in vivo, acute administration significantly decreased high‐fat diet consumption. Repeated administration of the compounds decreased body weight and more specifically, decreased the percentage of visceral adipose tissue (VAT) in obese mice. These results have confirmed small‐molecule NMUR2 agonists are efficacious in animal models to decrease fat content, food intake, and body weight, suggesting NMUR2 is a promising therapeutic target for metabolic disorders.

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Superagonism at G protein‐coupled receptors and beyond

Cited by 27 publications

References 89 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

A Photoswitchable Dualsteric Ligand Controlling Receptor Efficacy

Small‐Molecule Neuromedin U Receptor 2 Agonists Suppress Food Intake and Decrease Visceral Fat in Animal Models

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