In:
British Journal of Pharmacology, Wiley, Vol. 180, No. 4 ( 2023-02), p. 441-458
Abstract:
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 γ (PI3Kγ) −/− , and PI3Kγ 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 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. Conclusion and Implications Activation of neuronal PI3Kγ, 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.
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
Language:
English
Publisher:
Wiley
Publication Date:
2023
detail.hit.zdb_id:
2029728-2
SSG:
15,3
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