400 Cathepsin S Induces Inflammation and Pain via Biased Agonism of PAR2 and TRPV4

Protease-activated receptor-2: Role in asthma pathogenesis and utility as a biomarker of disease severity

“…Many of the studies we will review below use PAR-AP to study PAR-mediated effects, since unlike natural proteases they do not induce PARindependent effects. Among PARs, PAR 2 has a wide expression pattern (11) and has been linked to inflammation in the skin (12), gastrointestinal tract (13) and lungs (14), as well as in inflammatory pain (15).…”

Protease-activated receptor-2: Role in asthma pathogenesis and utility as a biomarker of disease severity

“…Many of the studies we will review below use PAR-AP to study PAR-mediated effects, since unlike natural proteases they do not induce PARindependent effects. Among PARs, PAR 2 has a wide expression pattern (11) and has been linked to inflammation in the skin (12), gastrointestinal tract (13) and lungs (14), as well as in inflammatory pain (15).…”

Spinal PAR2 Activation Contributes to Hypersensitivity Induced by Peripheral Inflammation in Rats

“…Cloning of the seven-transmembrane G protein-coupled receptor (GPCR) proteaseactivated receptor 2 (PAR2) [1] allowed a detailed investigation of its role in a number of physiological and pathophysiological processes, including acute and chronic inflammation and hypersensitivity induction [2][3][4][5][6][7]. Numerous endogenous proteases target PAR2 to cleave the extracellular amino terminus at canonical cleavage sites (trypsin and mast cell tryptase) [8] to activate canonical pathways of GPCR signaling or at distinct sites (neutrophil elastase or macrophage cathepsin S) to activate the biased mechanisms [7,9,10]. Several synthetic PAR2-activating peptides (PAR2 AP) were developed, and in our experiments, we used SLIGKV-NH2, which corresponds to the tethered ligand domain and mimics the canonical mechanism of activation by the endogenous activators [11,12].…”

Protease-activated receptor-2: Role in asthma pathogenesis and utility as a biomarker of disease severity

“…Many of the studies we will review below use PAR-AP to study PAR-mediated effects, since unlike natural proteases they do not induce PARindependent effects. Among PARs, PAR 2 has a wide expression pattern (11) and has been linked to inflammation in the skin (12), gastrointestinal tract (13) and lungs (14), as well as in inflammatory pain (15).…”

Spinal PAR2 Activation Contributes to Hypersensitivity Induced by Peripheral Inflammation in Rats

“…Cloning of the seven-transmembrane G protein-coupled receptor (GPCR) proteaseactivated receptor 2 (PAR2) [1] allowed a detailed investigation of its role in a number of physiological and pathophysiological processes, including acute and chronic inflammation and hypersensitivity induction [2][3][4][5][6][7]. Numerous endogenous proteases target PAR2 to cleave the extracellular amino terminus at canonical cleavage sites (trypsin and mast cell tryptase) [8] to activate canonical pathways of GPCR signaling or at distinct sites (neutrophil elastase or macrophage cathepsin S) to activate the biased mechanisms [7,9,10]. Several synthetic PAR2-activating peptides (PAR2 AP) were developed, and in our experiments, we used SLIGKV-NH2, which corresponds to the tethered ligand domain and mimics the canonical mechanism of activation by the endogenous activators [11,12].…”

Protease-activated receptor-2: Role in asthma pathogenesis and utility as a biomarker of disease severity

“…Many of the studies we will review below use PAR-AP to study PAR-mediated effects, since unlike natural proteases they do not induce PARindependent effects. Among PARs, PAR 2 has a wide expression pattern (11) and has been linked to inflammation in the skin (12), gastrointestinal tract (13) and lungs (14), as well as in inflammatory pain (15).…”

Spinal PAR2 Activation Contributes to Hypersensitivity Induced by Peripheral Inflammation in Rats

“…Cloning of the seven-transmembrane G protein-coupled receptor (GPCR) proteaseactivated receptor 2 (PAR2) [1] allowed a detailed investigation of its role in a number of physiological and pathophysiological processes, including acute and chronic inflammation and hypersensitivity induction [2][3][4][5][6][7]. Numerous endogenous proteases target PAR2 to cleave the extracellular amino terminus at canonical cleavage sites (trypsin and mast cell tryptase) [8] to activate canonical pathways of GPCR signaling or at distinct sites (neutrophil elastase or macrophage cathepsin S) to activate the biased mechanisms [7,9,10]. Several synthetic PAR2-activating peptides (PAR2 AP) were developed, and in our experiments, we used SLIGKV-NH2, which corresponds to the tethered ligand domain and mimics the canonical mechanism of activation by the endogenous activators [11,12].…”