Interaction between P2X3 and ERα/ERβ in ATP-mediated calcium signaling in mice sensory neurons

Emerging evidence support a role of purinergic P2X3 receptors in modulating nociceptive signaling in sensory neurons. Previously we showed that DRG neurons (L1-S1) express both ERα and ERβ receptors. In this study we investigated the expression of P2X3 receptors and the effect of 17β-estradiol (E2) on ATP-induced [Ca2+]i increase in DRG neurons collected from C57Bl/6J, ERαKO and ERβKO mice. Our data showed a significant decrease for P2X3 in ERαKO (all levels) and ERβKO (mostly observed in L1, L2, L4, and L6). Furthermore, 17β-estradiol (100 nM) significantly attenuated the ATP (10 μM)-induced [Ca2+]i in C57Bl/6J mice. ERs antagonist ICI 182,780 (1μM) blocked this attenuation. Homomeric P2X3 receptors are plentifully expressed in DRG neurons and contribute to nociceptive signals. α,β-me ATP which is a specific agonist of P2X2/3 receptors showed similar responses to the ATP-induced calcium increase in knock-out mice. A membrane-impermeable E-6-BSA (1μM) had the same effect as E2 suggesting action on the membrane. In DRG neurons from ERβKO and WT miceE2 attenuated the ATP/α,β-me ATP-induced [Ca2+]i fluxes but in DRG neurons from ERαKO mice, this hormone had no effect suggesting that this attenuation depends on membrane-associated ERα receptors. Together our data indicate an interaction between P2X3 and membrane-associated ERα in primary sensory neurons that may represent a novel mechanism to explain sex differences observed in clinical presentation of visceral nociceptive syndromes.