Potentiation of acid-sensing ion channel activity by the activation of 5-HT₂ receptors in rat dorsal root ganglion neurons.
ABSTRACT Acid-sensing ion channels (ASICs), as key sensors for extracellular protons, are expressed in nociceptive sensory neurons and contribute to signalling pain caused by tissue acidosis. ASICs are also the subject of various factors. Here, we further provide evidence that the activity of ASICs is potentiated by the activation of 5-HT₂ receptors in rat dorsal root ganglion neurons. A specific 5-HT₂ receptor agonist, α-methyl-5-HT, dose-dependently enhanced proton-gated currents with an EC₅₀ of 0.13 ± 0.07 nM. The α-methyl-5-HT enhancing effect on proton-gated currents was blocked by cyproheptadine, a 5-HT₂ receptor antagonist, and removed by intracellular dialysis of either GDP-β-S or protein kinase C inhibitor GF109203X. Moreover, α-methyl-5-HT altered acid-evoked membrane excitability of rat DRG neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, α-methyl-5-HT increased nociceptive responses to injection of acetic acid in rats. These results suggest that α-methyl-5-HT up-regulates the activity of ASICs via 5-HT₂ receptor and protein kinase C dependent signal pathways in rat primary sensory neurons and this potentiation contributed to acid- mediated pain in tissue injury and inflammation.