Allosteric modulation of protease-activated receptor signaling.
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.
Department of Pharmacology, School of Medicine, University of California, San Diego, Biomedical Sciences Building, Room 3044A, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA. joanntrejo@ucsd.edu
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D000494:Allosteric Regulation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D047108:Embryonic Development / Q000502:physiology; D006487:Hemostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D010455:Peptides / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D059748:Proteolysis / Q000187:drug effects; D044462:Receptors, Proteinase-Activated / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013917:Thrombin / Q000378:metabolism*; D013927:Thrombosis / Q000378:metabolism / Q000503:physiopathology
D010455:Peptides; D020033:Protein Isoforms; D044462:Receptors, Proteinase-Activated; D013917:Thrombin