PGE2 Modulates GABAA Receptors via an EP1 Receptor-Mediated Signaling Pathway
Aims: PGE<sub>2</sub> is one of the most abundant prostanoids in mammalian tissues, but its effect on neuronal receptors has not been well investigated. This study examines the effect of PGE<sub>2</sub> on GABA<sub>A</sub> receptor currents in rat cerebellar granule neurons. Methods: GABA<sub>A</sub> currents were recorded using a patch-clamp technique. Cell surface and total protein of GABA<sub>A</sub> β1/2/3 subunits was carried out by Western blot analysis. Results: Upon incubation of neurons with PGE<sub>2</sub> (1 µM) for 60 minutes, GABA<sub>A</sub> currents were significantly potentiated. This PGE<sub>2</sub>-driven effect could be blocked by PKC or CaMKII inhibitors as well as EP1 receptor antagonist, and mimicked by PMA or EP1 receptor agonist. Furthermore, Western blot data showed that PGE<sub>2</sub> did not increase the total expression level of GABA<sub>A</sub> receptors, but significantly increased surface levels of GABA<sub>A</sub> β1/2/3 subunits after 1 h of treatment. Consistently, both PKC and CaMKII inhibitors were able to reduce PGE<sub>2</sub>-induced increases in cell surface expression of GABA<sub>A</sub> receptors. Conclusion: Activation of either the PKC or CaMKII pathways by EP1 receptors mediates the PGE<sub>2</sub>-induced increase in GABA<sub>A</sub> currents. This suggests that upregulation of postsynaptic GABA<sub>A</sub> receptors by PGE<sub>2</sub> may have profound effects on cerebellar functioning under physiological and pathological conditions.