Potentiation of acid-sensing ion channel currents by EGF/EGFR signaling in rat dorsal root ganglion neurons.

The epidermal growth factor receptor (EGFR) is located in primary sensory neurons and has been implicated in pain processing. However, its mechanism is still not well understood. The aim of the investigation is to determine whether EGFR signaling affects pain-associated ion channels in nociceptive dorsal root ganglion (DRG) neurons. Herein, we reported that the electrophysiological activity of acid-sensing ion channels (ASICs) was enhanced by epidermal growth factor (EGF) in rat DRG neurons. The application of EGF for 5 min concentration-dependently increased acid-evoked ASIC currents. EGF enhanced the ASIC's maximum responses to acidic stimuli without altering its sensitivity. EGFR did appear to be involved in the EGF-mediated potentiation of ASIC currents, since the potentiation was blocked by the EGFR kinase inhibitor AG556. The EGF-mediated potentiation was ERK-dependent, since the potentiation was prevented by the ERK inhibitor U0126. In contrast, the JNK inhibitor SP600125 and the p38 inhibitor SB202190 had no effect on the EGF-mediated potentiation. Moreover, EGF increased the number of acid-evoked action potentials. Finally, injection of EGF into rat paws exacerbated acid-induced nociceptive behavior in dose-dependent manner. The present results that enhanced functional activity of ASICs by EGF/EGFR signaling provided evidence that EGF/EGFR signaling is a promising target for the treatment of pain caused by tissue acidification.