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Prostaglandin EP3 receptor activation is antinociceptive in sensory neurons via PI3Kγ, AMPK and GRK2.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2023 Feb; Vol. 180 (4), pp. 441-458. Date of Electronic Publication: 2022 Nov 17. - Publication Year :
- 2023
-
Abstract
- Background and Purpose: Prostaglandin E <subscript>2</subscript> is considered a major mediator of inflammatory pain, by acting on neuronal G <subscript>s</subscript> protein-coupled EP2 and EP4 receptors. However, the neuronal EP3 receptor, colocalized with EP2 and EP4 receptor, is G <subscript>i</subscript> protein-coupled and antagonizes the pronociceptive prostaglandin E <subscript>2</subscript> effect. Here, we investigated the cellular signalling mechanisms by which the EP3 receptor reduces EP2 and EP4 receptor-evoked pronociceptive effects in sensory neurons.<br />Experimental Approach: Experiments were performed on isolated and cultured dorsal root ganglion (DRG) neurons from wild type, phosphoinositide 3-kinase γ (PI3Kγ) <superscript>-/-</superscript> , and PI3Kγ <superscript>kinase dead (KD)/KD</superscript> 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.<br />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 PI3Kγ, and adenosine monophosphate activated protein kinase (AMPK) is involved. By contrast, inhibition of EP4 receptor-evoked pronociceptive effect is independent on PI3Kγ and mediated through activation of G protein-coupled receptor kinase 2 (GRK2), which enhances the internalization of the EP4 receptor after ligand binding.<br />Conclusion and Implications: Activation of neuronal PI3Kγ, AMPK, and GRK2 by EP3 receptor activation limits cAMP-dependent pain generation by prostaglandin E <subscript>2</subscript> . These new insights hold the potential for a novel approach in pain therapy.<br /> (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
- Subjects :
- Animals
Mice
Phosphatidylinositol 3-Kinase
Phosphatidylinositol 3-Kinases
Dinoprostone pharmacology
Dinoprostone metabolism
Receptors, Prostaglandin E, EP4 Subtype
Receptors, Prostaglandin E, EP2 Subtype
Sensory Receptor Cells metabolism
Pain
Analgesics
Receptors, Prostaglandin E, EP3 Subtype metabolism
Prostaglandins
AMP-Activated Protein Kinases
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 180
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 36245399
- Full Text :
- https://doi.org/10.1111/bph.15971