The Sensitization Effect Of PAR₂ Signal On ASIC3

Objective:Tissue acidosis and inflammatory mediators play critical roles in pain.Pro-inflammatory agents trypsin and tryptase cleave and activate proteinase-activated receptor 2?PAR₂?expressed on sensory nerves,which is involved in peripheral mechanisms of inflammation and pain.Extracellular acidosis activates acid-sensing ion channel 3?ASIC3?to trigger pain sensation.Here,we show whether there's a functional interaction between PAR₂ and ASIC3,which could contribute to acidosis-induced nociception.Methods:Electrophysiological experiments were performed on both rat DRG neurons and Chinese hamster ovary?CHO?cells expressing ASIC3 and PAR₂.Nociceptive behavior was induced by acetic acid in rats.Results:PAR₂-AP,PAR₂-activating peptide,concentration-dependently increased the ASIC3 currents in CHO cells transfected with ASIC3 and PAR₂.The proton concentration–response relationship was not changed,but that the maximal response increased 58.7±3.8%after pretreatment of PAR₂-AP.PAR₂ mediated the potentiation of ASIC3currents via an intracellular cascade.PAR₂-AP potentiation of ASIC3 currents disappeared after inhibition of intracellular G protein,PLC,PKC,or PKA signaling.Moreover,PAR₂ activation increased proton-evoked currents and spikes mediated by ASIC3 in rat dorsal root ganglion neurons.Finally,peripheral administration of PAR₂-AP dose-dependently exacerbated acidosis-induced nocifensive behaviors in rats.Conclusions:These results indicated that PAR₂ signaling sensitized ASIC3,which may contribute to acidosis-induced nociception.These represent a novel peripheral mechanism underlying PAR₂ involvement in hyperalgesia by sensitizing ASIC3 in primary sensory neurons.