Metabotropic regulation of ATP-gated P2X3 receptors

Abstract

Among the ATP-gated channels, the P2X3 subtype is exclusively expressed in nociceptors of dorsal root ganglia (DRG) and trigeminal ganglia, where it plays a major role in enhanced pain sensation observed in chronic pain states. We tested the hypothesis that P2X3 receptors are modulated by metabotropic receptors, such as 5-HT2A, mG1uR5 and trkA, leading to increased P2X3-mediated currents. Double fluorescence labeling confirmed that P2X3-expressing neurons are labeled by the lectin IB4 and we showed that 5-HT2A and mGluR5 receptors, but not trkA, are expressed in a fraction of IB4-positive neurons. Using confocal microscopy, we examined the subcellular distribution of P2X3 and we observed that 5-HT induced a translocation of P2X3 labeling in a significant number of neurons. In Xenopus oocytes, we recorded a short-lasting and kinase-dependent potentiation of P2X3 currents by activation of co-expressed 5-HT2A and mGluR5 receptors. The data presented here show that both 5-HT2A and mG1uR5 are potential modulators of P2X3 receptors in a subset of nociceptors in DRG