The protease-activated receptors (PARs) are G protein-coupled receptors (GPCRs) that are uniquely activated
by proteolysis. PARs mediate hemostasis, thrombosis, inflammation, embryonic development and progression of certain
malignant cancers. The family of PARs include four members: PAR1, PAR2, PAR3 and PAR4. PARs harbor a cryptic
ligand sequence within their N-terminus that is exposed following proteolytic cleavage. The newly formed PAR Nterminus
functions as a tethered ligand that binds intramolecularly to the receptor to trigger transmembrane signaling. This
unique mechanism of activation would indicate that regardless of the activating protease, cleavage of PARs would
unmask a tethered ligand sequence that would induce a similar active receptor conformation and signaling response.
However, this is not the case. Recent studies demonstrate that PARs can be differentially activated by synthetic peptide
agonists, proteases or through dimerization, that ultimately result in distinct cellular responses. In some cases, allosteric
modulation of PARs involves compartmentalization in caveolae, plasma membrane microdomains enriched in cholesterol.
Here, we discuss some mechanisms that lead to allosteric modulation of PAR signaling.
Keywords: Thrombin, GPCR, G protein, caveolae, palmitoylation, kallikriens, guanine nucleotide, SFLLRN, TFLLRNPNDK, fibroblast-to-myofibroblast
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