Signaling profile of a new PAR2 inhibitor with anti‐inflammatory effects
Notice bibliographique
Résumé
The protease‐activated receptor‐2 (PAR2) belongs to an atypical subfamily of G protein–coupled receptors (GPCR), activated by the proteolytic cleavage of their N‐terminal region by enzymes such as thrombin or trypsin. This cleavage exposes a region of the N‐terminal extracellular domain (the “tethered ligand”) to bind to the extracellular loop 2 and others domains of the PAR2. This results in the stabilization of an active conformation of the receptor. Short synthetic peptides mimicking the tethered ligand sequence are also able to activate PAR2. This subfamily of GPCR is largely involved in inflammatory responses and may therefore represent a promising therapeutic target for the treatment of immune‐mediated inflammatory diseases. It is now recognized that activated‐GPCRs can engage multiple signaling pathways and that specific ligands can selectively promote the engagement of different subsets of these pathways. We therefore characterized the functional selectivity of PAR2 modulators in the context of their potential action as anti‐inflammatory drugs. Elucidating the various signaling pathways should help directed targeting in the quest for therapeutic efficacy; and reciprocally minimize undesirable side effects. For this, we have established the exhaustive signaling signatures of PAR2 modulators using bioluminescence resonance energy transfer (BRET)‐based biosensors in heterologous and native human cell based systems. First, the repertoire of signaling pathways that can be triggered by trypsin and a PAR2 activating peptide (SLIGKV‐NH 2 ) were established. We then identified a compound with a particularly interesting signaling profile among the different modulators tested. Indeed, we showed that compound C5 acts as a negative allosteric modulator (NAM) for the Gα 13 /Gα q /DAG/Ca 2+ /PKC signaling pathways activated by both agonists (SLIGKV‐NH 2 or trypsin) whereas it has no effect on Gα 12 /Gα i2 /Gα oA /Gα oB pathways activated by trypsin or SLIGKV‐NH 2 and acts as a positive allosteric modulator (PAM) for βarrestin2 recruitment induced by the short peptide. Using a mouse BRET‐based signaling array, we showed that C5 presents a similar signaling profile on the mouse PAR2, establishing inter‐species translation of the results obtained with human receptor in rodent model. Finally, we have evaluated the anti‐inflammatory activity of C5 by measuring its impact on (i) cytokines secretion induced by PAR2 in HCT‐116 cells and (ii) volume of paw edema in rodent inflammatory models. Our preliminary data indicated that C5 presents anti‐inflammatory properties in vitro and in vivo . Overall, our results suggest that C5, by selectively inhibiting PAR2‐induced Gα 13 /Gα q /DAG/Ca 2+ /PKC signaling pathways, leads to the anti‐inflammatory effects observed in vitro and in vivo . PAR2 functional selectivity highlights the opportunity to design new drugs that specifically block PAR2‐activated signaling pathway in disease, without affecting beneficial PAR2 signaling in normal physiology. Support or Funding Information Canadian Institutes of Health Research This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».