Metabotropic regulation of ATP-gated P2X3 receptors

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

Effect of Human Genetic Variability on Gene Expression in Dorsal Root Ganglia and Association with Pain Phenotypes

Dorsal root ganglia (DRG) relay sensory information to the brain, giving rise to the perception of pain, disorders of which are prevalent and burdensome. Here, we mapped expression quantitative trait loci (eQTLs) in a collection of human DRGs. DRG eQTLs were enriched within untranslated regions of coding genes of low abundance, with some overlapping with other brain regions and blood cell cis-eQTLs. We confirm functionality of identified eQTLs through their significant enrichment within open chromatin and highly deleterious SNPs, particularly at the exon level, suggesting substantial contribution of eQTLs to alternative splicing regulation. We illustrate pain-related genetic association results explained by DRG eQTLs, with the strongest evidence for contribution of the human leukocyte antigen (HLA) locus, confirmed using a mouse inflammatory pain model. Finally, we show that DRG eQTLs are found among hits in numerous genome-wide association studies, suggesting that this dataset will help address pain components of non-pain disorders