Neutrophil elastase acts as a biased agonist for proteinase-activated receptor-2 (PAR2) |
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Authors: | Ramachandran Rithwik Mihara Koichiro Chung Hyunjae Renaux Bernard Lau Chang S Muruve Daniel A DeFea Kathryn A Bouvier Michel Hollenberg Morley D |
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Institution: | Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada. rramacha@ucalgary.ca |
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Abstract: | Human neutrophil proteinases (elastase, proteinase-3, and cathepsin-G) are released at sites of acute inflammation. We hypothesized that these inflammation-associated proteinases can affect cell signaling by targeting proteinase-activated receptor-2 (PAR(2)). The PAR family of G protein-coupled receptors is triggered by a unique mechanism involving the proteolytic unmasking of an N-terminal self-activating tethered ligand (TL). Proteinases can either activate PAR signaling by unmasking the TL sequence or disarm the receptor for subsequent enzyme activation by cleaving downstream from the TL sequence. We found that none of neutrophil elastase, cathepsin-G, and proteinase-3 can activate G(q)-coupled PAR(2) calcium signaling; but all of these proteinases can disarm PAR(2), releasing the N-terminal TL sequence, thereby preventing G(q)-coupled PAR(2) signaling by trypsin. Interestingly, elastase (but neither cathepsin-G nor proteinase-3) causes a TL-independent PAR(2)-mediated activation of MAPK that, unlike the canonical trypsin activation, does not involve either receptor internalization or recruitment of β-arrestin. Cleavage of synthetic peptides derived from the extracellular N terminus of PAR(2), downstream of the TL sequence, demonstrated distinct proteolytic sites for all three neutrophil-derived enzymes. We conclude that in inflammation, neutrophil proteinases can modulate PAR(2) signaling by preventing/disarming the G(q)/calcium signal pathway and, via elastase, can selectively activate the p44/42 MAPK pathway. Our data illustrate a new mode of PAR regulation that involves biased PAR(2) signaling by neutrophil elastase and a disarming/silencing effect of cathepsin-G and proteinase-3. |
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Keywords: | Calcium G Protein-coupled Receptors (GPCRs) MAP Kinases (MAPKs) Neutrophil Protease Biased Agonist Biased Signaling Elastase Protease-activated Receptors Proteinase-activated Receptors |
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