Proteinase-activated receptors (PARs) represent a unique subclass of G-protein-coupled receptors of which four family members have now been cloned from a number of species. The novel mechanism of receptor activation involves the proteolytic unmasking of a cryptic N-terminal receptor sequence that, remaining tethered, binds to and triggers receptor function. In addition, short (five to six amino acids) synthetic peptides, based on the proteolytically revealed motif, can activate PARs without the unmasking of the tethered ligand. This article summarizes the experiments leading to the pharmacological characterization and cloning of the four PAR family members and provides a rationale for their designation by the acronym "PAR". The ability to distinguish among the PARs pharmacologically 1) with selective proteinase activators, 2) with receptor-selective peptide agonists, and 3) with peptide and nonpeptide antagonists is discussed, as are the molecular mechanisms of receptor activation and desensitization/internalization. Finally, the potential physiological roles of the PARs, which are widely distributed in many organs in the settings of tissue injury, repair, and remodeling, including embryogenesis and oncogenesis are discussed, and the newly appreciated roles of proteinases as signaling molecules that can act as either functional agonists or antagonists are highlighted.

Proteinases like thrombin, trypsin and tissue kallikreins are now known to regulate cell signaling by cleaving and activating a novel family of G‐protein‐coupled proteinase‐activated receptors (PARs 1–4) via exposure of a tethered receptor‐triggering ligand. On their own, short synthetic PAR‐selective PAR‐activating peptides (PAR‐APs) mimicking the tethered ligand sequences can activate PARs 1, 2 and 4 and cause physiological responses bothin vitroandin vivo.Using the PAR‐APs as sentinel probesin vivo, it has been found that PAR activation can affect the vascular, renal, respiratory, gastrointestinal, musculoskeletal and nervous systems (both central and peripheral nervous system) and can promote cancer metastasis and invasion. In general, responses triggered by PARs 1, 2 and 4 are in keeping with an innate immune inflammatory response, ranging from vasodilatation to intestinal inflammation, increased cytokine production and increased or decreased nociception. Further, PARs have been implicated in a number of disease states, including cancer and inflammation of the cardiovascular, respiratory, musculoskeletal, gastrointestinal and nervous systems. In addition to activating PARs, proteinases can cause hormone‐like effects by other signalling mechanisms, like growth factor receptor activation, that may be as important as the activation of PARs. We, therefore, propose that the PARs themselves, their activating serine proteinases and their associated signalling pathways can be considered as attractive targets for therapeutic drug development. Thus, proteinases in general must now be considered as ‘hormone‐like’ messengers that can signal eitherviaPARs or other mechanisms.British Journal of Pharmacology(2008)153, S263–S282; doi:10.1038/sj.bjp.0707507; published online 3 December 2007

Serine proteinases like thrombin can signal to cells by the cleavage/activation of proteinase-activated receptors (PARs). Although thrombin is a recognized physiological activator of PAR₁ and PAR₄, the endogenous enzymes responsible for activating PAR₂ in settings other than the gastrointestinal system, where trypsin can activate PAR₂, are unknown. We tested the hypothesis that the human tissue kallikrein (hK) family of proteinases regulates PAR signaling by using the following: 1) a high pressure liquid chromatography (HPLC)-mass spectral analysis of the cleavage products yielded upon incubation of hK5, -6, and -14 with synthetic PAR N-terminal peptide sequences representing the cleavage/activation motifs of PAR₁, PAR₂, and PAR₄; 2) PAR-dependent calcium signaling responses in cells expressing PAR₁, PAR₂, and PAR₄ and in human platelets; 3) a vascular ring vasorelaxation assay; and 4) a PAR₄-dependent rat and human platelet aggregation assay. We found that hK5, -6, and -14 all yielded PAR peptide cleavage sequences consistent with either receptor activation or inactivation/disarming. Furthermore, hK14 was able to activate PAR₁, PAR₂, and PAR₄ and to disarm/inhibit PAR₁. Although hK5 and -6 were also able to activate PAR₂, they failed to cause PAR₄-dependent aggregation of rat and human platelets, although hK14 did. Furthermore, the relative potencies and maximum effects of hK14 and -6 to activate PAR₂-mediated calcium signaling differed. Our data indicate that in physiological settings, hKs may represent important endogenous regulators of the PARs and that different hKs can have differential actions on PAR₁, PAR₂, and PAR₄.

Proteinase-activated receptors (PARs) are a subfamily of G protein-coupled receptors (GPCRs) with four members, PAR₁, PAR₂, PAR₃and PAR₄, playing critical functions in hemostasis, thrombosis, embryonic development, wound healing, inflammation and cancer progression. PARs are characterized by a unique activation mechanism involving receptor cleavage by different proteinases at specific sites within the extracellular amino-terminus and the exposure of amino-terminal “tethered ligand“ domains that bind to and activate the cleaved receptors. After activation, the PAR family members are able to stimulate complex intracellular signalling networks via classical G protein-mediated pathways and beta-arrestin signalling. In addition, different receptor crosstalk mechanisms critically contribute to a high diversity of PAR signal transduction and receptor-trafficking processes that result in multiple physiological effects.In this review, we summarize current information about PAR-initiated physical and functional receptor interactions and their physiological and pathological roles. We focus especially on PAR homo- and heterodimerization, transactivation of receptor tyrosine kinases (RTKs) and receptor serine/threonine kinases (RSTKs), communication with other GPCRs, toll-like receptors and NOD-like receptors, ion channel receptors, and on PAR association with cargo receptors. In addition, we discuss the suitability of these receptor interaction mechanisms as targets for modulating PAR signalling in disease.

Although it has been known since the 1960s that trypsin and chymotrypsin can mimic hormone action in tissues, it took until the 1990s to discover that serine proteinases can regulate cells by cleaving and activating a unique four‐member family ofGPCRs known as proteinase‐activated receptors (PARs).PARactivation involves the proteolytic exposure of itsN‐terminal receptor sequence that folds back to function as a ‘tethered’ receptor‐activating ligand (TL). A keyN‐terminal arginine in each ofPARs1 to 4 has been singled out as a target for cleavage by thrombin (PARs1, 3 and 4), trypsin (PARs2 and 4) or other proteases to unmask theTLthat activates signalling viaG_q, G_iorG_12/13. Similarly, synthetic receptor‐activating peptides, corresponding to the exposed ‘TLsequences’ (e.g.SFLLRN—, forPAR1orSLIGRL— forPAR2) can, like proteinase activation, also drive signalling viaG_q,G_iandG_12/13, without requiring receptor cleavage. Recent data show, however, that distinct proteinase‐revealed ‘non‐canonical’PARtethered‐ligand sequences andPAR‐activating agonist and antagonist peptide analogues can induce ‘biased’PARsignalling, for example, viaG_12/13‐MAPKinase instead ofG_q‐calcium. This overview summarizes implications of this ‘biased’ signalling byPARagonists and antagonists for the recognized roles thePARs play in inflammatory settings.Linked Articles: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2014.171.issue‐5