| First Author | König C | Year | 2023 |
| Journal | Br J Pharmacol | Volume | 180 |
| Issue | 4 | Pages | 441-458 |
| PubMed ID | 36245399 | Mgi Jnum | J:350314 |
| Mgi Id | MGI:7662464 | Doi | 10.1111/bph.15971 |
| Citation | Konig C, et al. (2023) Prostaglandin EP3 receptor activation is antinociceptive in sensory neurons via PI3Kgamma, AMPK and GRK2. Br J Pharmacol 180(4):441-458 |
| abstractText | BACKGROUND AND PURPOSE: Prostaglandin E(2) is considered a major mediator of inflammatory pain, by acting on neuronal G(s) protein-coupled EP2 and EP4 receptors. However, the neuronal EP3 receptor, colocalized with EP2 and EP4 receptor, is G(i) protein-coupled and antagonizes the pronociceptive prostaglandin E(2) effect. Here, we investigated the cellular signalling mechanisms by which the EP3 receptor reduces EP2 and EP4 receptor-evoked pronociceptive effects in sensory neurons. EXPERIMENTAL APPROACH: Experiments were performed on isolated and cultured dorsal root ganglion (DRG) neurons from wild type, phosphoinositide 3-kinase gamma (PI3Kgamma)(-/-) , and PI3Kgamma(kinase dead (KD)/KD) mice. For subtype-specific stimulations, we used specific EP2, EP3, and EP4 receptor agonists from ONO Pharmaceuticals. As a functional readout, we recorded TTX-resistant sodium currents in patch-clamp experiments. Western blots were used to investigate the activation of intracellular signalling pathways. EP4 receptor internalization was measured using immunocytochemistry. KEY RESULTS: Different pathways mediate the inhibition of EP2 and EP4 receptor-dependent pronociceptive effects by EP3 receptor stimulation. Inhibition of EP2 receptor-evoked pronociceptive effect critically depends on the kinase-independent function of the signalling protein PI3Kgamma, and adenosine monophosphate activated protein kinase (AMPK) is involved. By contrast, inhibition of EP4 receptor-evoked pronociceptive effect is independent on PI3Kgamma and mediated through activation of G protein-coupled receptor kinase 2 (GRK2), which enhances the internalization of the EP4 receptor after ligand binding. CONCLUSION AND IMPLICATIONS: Activation of neuronal PI3Kgamma, AMPK, and GRK2 by EP3 receptor activation limits cAMP-dependent pain generation by prostaglandin E(2) . These new insights hold the potential for a novel approach in pain therapy. |
