Abstract
Mast cell degranulation and evoked protease‐activated receptor 2 (PAR2) activity has been implicated in inflammation and chronic pain. Both protein kinase C and cAMP‐dependent protein kinase (PKA) transduce activated PAR2 signaling. However, it is unclear how PKA is activated by PAR2. In this study, we tested the hypothesis that activated PAR2 modulates the activation of PKA in a temporal manner. Acute treatment of HEK293 cells with PAR2 agonists SLIGRL−NH2 or the small molecule AC264613 resulted in a time and dose dependent inhibition of cAMP accumulation that could be reversed by administering a PAR2 antagonist FSLLRY−NH2. Furthermore, prolonged exposure of PAR2 to its agonists led to a paradoxical time‐dependent upregulation of intracellular cAMP levels. These effects are abrogated by pre‐treatment with pertussis toxin and suggest that PAR2 is coupled to the Gi protein. These results suggest a mechanism for the activation of PKA and affirm PAR2 as a significant regulator of inflammation and pain signaling.
Published Version
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