Fig. 10.

Mechanisms of protease- and PAR₂-induced hyperexcitability of nociceptors. After activation by canonical mechanisms, PAR₂ signals at the plasma membrane to activate PKC, which mediates initial hyperexcitability (1). PAR₂ then undergoes clathrin-, dynamin-, and βARR-dependent endocytosis (2). PAR₂ continues to signal from endosomes by βARR- and Gα_q-mediated mechanisms to activate ERK, which mediates persistent hyperexcitability. After activation by biased mechanisms, PAR₂ signals from the plasma membrane to activate adenylyl cyclase (AC) and PKA, which mediate the initial and persistent hyperexcitability (3). Kinases may regulate the activity of TRP channels and voltage-gated ion channels, to control nociceptor hyperexcitability (4).