Prostaglandin E2 Potentiation of P2X3 Receptor Mediated Currents in Dorsal Root Ganglion Neurons

Congying Wang,Guang-Wen Li,Li-Yen Mae Huang

doi:10.1186/1744-8069-3-22

Congying Wang, Guang-Wen Li + Show 1 more

Open Access

https://doi.org/10.1186/1744-8069-3-22

Copy DOI

Abstract

Prostaglandin E2 (PGE2) is a well-known inflammatory mediator that enhances the excitability of DRG neurons. Homomeric P2X3 and heteromeric P2X2/3 receptors are abundantly expressed in dorsal root ganglia (DRG) neurons and participate in the transmission of nociceptive signals. The interaction between PGE2 and P2X3 receptors has not been well delineated. We studied the actions of PGE2 on ATP-activated currents in dissociated DRG neurons under voltage-clamp conditions. PGE2 had no effects on P2X2/3 receptor-mediated responses, but significantly potentiated fast-inactivating ATP currents mediated by homomeric P2X3 receptors. PGE2 exerted its action by activating EP3 receptors. To study the mechanism underlying the action of PGE2, we found that the adenylyl cyclase activator, forskolin and the membrane-permeable cAMP analogue, 8-Br-cAMP increased ATP currents, mimicking the effect of PGE2. In addition, forskolin occluded the enhancement produced by PGE2. The protein kinase A (PKA) inhibitors, H89 and PKA-I blocked the PGE2 effect. In contrast, the PKC inhibitor, bisindolymaleimide (Bis) did not change the potentiating action of PGE2. We further showed that PGE2 enhanced α,β-meATP-induced allodynia and hyperalgesia and the enhancement was blocked by H89. These observations suggest that PGE2 binds to EP3 receptors, resulting in the activation of cAMP/PKA signaling pathway and leading to an enhancement of P2X3 homomeric receptor-mediated ATP responses in DRG neurons.

Highlights

ATP plays a prominent role in nociception
PGE2 potentiates P2X3 receptor-mediated ATP responses We first determined the effects of PGE2 on ATP or its analog, α,β-meATP-activated currents in dorsal root ganglion (DRG) neurons
PGE2 (1 μM, 2 min application) enhanced the peak amplitude of both fast-inactivating ATP- and α,β-meATP-evoked currents (Fig. 1B). These results suggest that PGE2 potentiates homomeric P2X3 receptor-mediated responses

Summary

Introduction

ATP plays a prominent role in nociception. Its application onto human skin elicits pain [1,2]. Recent studies of purinergic receptors in primary sensory dorsal root ganglion (DRG) neurons demonstrate that ATP gives rise to nociception by activating P2X receptors in primary sensory DRG neurons [7,8,9]. P2X2 and P2X3 receptors are the major receptor types selectively expressed in peripheral and central terminals and the somata of DRG neurons [11,12,13,14]. These neurons are small (diameter d < 25 μm) and medium (25 < d < 40 μm) in size, bind isolectin B4 and express vanilloid TRPV1 receptors [15,16,17,18].

Methods

Results

Conclusion