Differential expression and pharmacology of native p2× receptors in rat and primate sensory neurons

Abstract

Evidence suggesting the involvement of P2×2 and P2×3 in chronic pain has been obtained mostly from rodent models. Here we show that rodents may be poor predictors of P2×3 pharmacology in human. We demonstrate that monkey and human dorsal root ganglion (DRG) neurons do not express appreciable levels of P2×2 subunit, contrary to rat sensory neurons. Additionally, we report functional P2×3 activity in monkey DRG neurons and confirm the absence of functional P2×2/3 receptors. Interestingly, native P2X3 receptors in rat and monkeyDRGsshow similar agonist potency, but different antagonist potencies forTNP-ATP[2-O-(2,4,6-trinitrophenyl)-ATP] and RO51. This unexpected difference in antagonist potency was confirmed by comparing rat and human P2×3 receptors in HEK293 cells. Mutagenesis studies reveal that two extracellular residues, A197 and T202, are synergistically responsible for the potency drop in primate P2×3 receptors. These results uncover species-specific P2×3 pharmacology and identify key mechanisms impacting the translatability of potential analgesics targeting P2X3 receptors. ©2012 the authors.