Protease-activated Receptor 2 (PAR2) Protein and Transient Receptor Potential Vanilloid 4 (TRPV4) Protein Coupling Is Required for Sustained Inflammatory Signaling*

Abstract

Background: Receptors activate channels of sensory nerves to cause inflammation and pain by unknown mechanisms. Results: Protease-activated receptor 2 (PAR 2 ) stimulated transient receptor potential vanilloid 4 (TRPV4) by generation of channel agonists. This required a key TRPV4 tyrosine and induced inflammation. Conclusion: PAR 2 opens TRPV4 by functional coupling. Significance: Antagonism of PAR 2 -TRPV4 coupling could alleviate inflammation and pain.

Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain

“…However, the mechanism of coupling is agonist-dependent. Trypsin-activated PAR 2 stimulates TRPV4 in sensory neurons by PKC-and tyrosine kinase-dependent processes, and by the generation of arachidonic acid metabolites (8,9). In contrast, diesel exhaust particles can activates the PAR 2 -TRPV4 axis in airway epithelial cells by a G i/o and phosphatidylinositide 3-kinase-dependent mechanism (64).…”

“…PAR 2 constructs for expression in mammalian cells have been described (9,15). Human embryonic kidney (HEK) 293 cells and sarcoma virus-transformed rat kidney epithelial (KNRK) cells were maintained in DMEM with 10% fetal bovine serum (FBS) and 1% penicillin and streptomycin.…”

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

“…In a very recent study, authors demonstrated a functional coupling between PAR 2 and TRPV4 [72]. In fact, PAR 2 activation induced the production of endogenous activators of TRPV4 via cytochrome epoxygenase activation [72]. This functional coupling was not observed between PAR 2 and TRPA1 [72].…”

“…Thus, the electrophysiological recordings from splanchnic afferents did not reveal that PAR 2 sensitizes TRPA1 [71] but the behavioral studies of awake animals showed sensitization [67]. In a very recent study, authors demonstrated a functional coupling between PAR 2 and TRPV4 [72]. In fact, PAR 2 activation induced the production of endogenous activators of TRPV4 via cytochrome epoxygenase activation [72].…”

“…In fact, PAR 2 activation induced the production of endogenous activators of TRPV4 via cytochrome epoxygenase activation [72]. This functional coupling was not observed between PAR 2 and TRPA1 [72].…”