Proteinase-activated receptors

Overview

Proteinase-activated receptors (PARs) are unique members of the GPCR superfamily activated by proteolytic cleavage of their amino terminal exodomains. Agonist proteinase-induced hydrolysis unmasks a tethered ligand (TL) at the exposed amino terminus, which acts intramolecularly at the binding site in the body of the receptor to effect transmembrane signalling. TL sequences at human PAR1-4 are SFLLRN-NH2, SLIGKV-NH2, TFRGAP-NH2 and GYPGQV-NH2, respectively. With the exception of PAR3, synthetic peptides with these sequences (as carboxyl terminal amides) are able to act as agonists at their respective receptors. Several proteinases, including neutrophil elastase, cathepsin G and chymotrypsin can have inhibitory effects at PAR1 and PAR2 such that they cleave the exodomain of the receptor without inducing activation of Gαq-coupled calcium signalling, thereby preventing activation by activating proteinases but not by agonist peptides. Neutrophil elastase (NE) cleavage of PAR1 and PAR2 can however activate MAP kinase signaling by exposing a TL that is different from the one revealed by trypsin [1]. PAR2 activation by NE regulates inflammation and pain responses [2,3] and triggers mucin secretion from airway epithelial cells [4].

References

  1. Ramachandran R, Noorbakhsh F, Defea K, et al. Targeting proteinase-activated receptors: therapeutic potential and challenges. Nat Rev Drug Discov 2012;11:69-86.
  2. Zhao P, Lieu T, Barlow N, et al. Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain. J Biol Chem 2015;290:13875-87.
  3. Muley MM, Reid AR, Botz B, et al. Neutrophil elastase induces inflammation and pain in mouse knee joints via activation of proteinase-activated receptor-2. Br J Pharmacol 2016;173:766-77.
  4. Zhou J, Perelman JM, Kolosov VP, et al. Neutrophil elastase induces MUC5AC secretion via protease-activated receptor 2. Mol Cell Biochem 2013;377:75-85.
Excerpt from IUPHAR/BPS Guide to Pharmacology