Associate editor: Peter MolenaarStructure, function and pathophysiology of protease activated receptors
Introduction
The four PAR family members (designated PAR1, PAR2, PAR3 and PAR4 (Hollenberg & Compton, 2002)2) belong to the broader G protein coupled receptor (GPCR) super family. In contrast with other GPCRs, PARs are not activated in vivo by binding of a soluble ligand but, instead, are triggered by proteases which cleave extracellularly within the PAR amino terminus. This cleavage exposes a new amino terminus that binds intramolecularly to activate the receptor and induce intracellular signal transduction. As described below, although the PARs are homologous and have overlapping tissue expression patterns, the functions of each receptor, and their roles in physiology and disease, are distinct and coordinated by an intricate array of binding proteins and post-translation modifications that regulate PAR trafficking, sub-cellular localization, signal transduction and termination, and receptor degradation.
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Structural features and activation mechanisms
The PARs are encoded by genes that map to either a gene cluster on chromosome 5q13 (F2R encoding PAR1, F2RL1 encoding PAR2 and F2RL2 encoding PAR3) or chromosome 19p12 (F2RL3 encoding PAR4; Schmidt et al., 1997, Kahn et al., 1998a). Each gene spans two exons, the first encoding the signal peptide and the second the mature protein (Kahn et al., 1998a). As shown in Fig. 1, the PARs contain seven transmembrane (TM) helices, an extracellular amino terminal domain encompassing a signal peptide of
Agonists and antagonists
The various cellular effects stimulated in vivo via the PAR family are most often mediated by trypsin-like serine proteases that cleave on the carboxyl terminal side of arginine and lysine residues (Hansen et al., 2008, Ramsay et al., 2008b). Cleavage by these proteases, other than at this activation site, results in receptor inactivation (or disarming). In this section we describe the proteases so far known to function as PAR agonists and those that disarm these receptors. The general features
Molecular aspects of PAR function
PAR-mediated signal transduction occurs via ‘conventional’ intracellular coupling to specific G protein subunits and, also for PAR2, via G-protein independent pathways involving β-arrestin scaffolding (Sun et al., 2007, Defea, 2008). It is now apparent that these pathways are modulated at multiple levels including receptor translocation to, and localisation within, the plasma membrane, the properties of the agonist, molecular events following receptor activation including signal termination,
Physiological and pathological roles
Soon after PAR1 was cloned Coughlin and colleagues were able to establish that, in addition to activation by proteolytic cleavage and exposure and intramolecular binding of the TL, PAR1 could also be activated by a short synthetic peptide mimicking the sequence of the revealed TL (Vu et al., 1991, Scarborough et al., 1992). As described above, subtype-selective short synthetic peptides that activate each PAR are known (with the possible exception of PAR3) and have proven to be invaluable in
Conclusion
Much progress has been made over the last 20 years through molecular, biochemical, pharmacological and animal based studies in understanding aspects of the intricate mechanisms regulating PARs and the roles these receptors have in normal physiology and disease. This level of understanding has supported the first attempts to generate PAR1-targeted therapeutics designed to treat a number of cardiovascular ailments. Further effort is required to provide a more complete understanding of PAR biology
Acknowledgments
This work was supported by grants from the National Health and Medical Research Council of Australia (569595 (DPF), 614206 (JDH), APP1000745 (DPF)), the Cancer Council Queensland (JDH), the Australian Research Council (DP1093245 (DPF)) and the Canadian Institutes of Health Research (MDH), an ARC Federation Fellowship (DPF), and Australian Post-Graduate Award Scholarships (MNA and MKY), an Alberta Hertiage Foundation for Medical Research Post-Doctoral Fellowship (RR) and a University of
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The term “protease activated receptor” is used in preference to “proteinase activated receptor”.