PGE2 Modulates GABAA Receptors via an EP1 Receptor-Mediated Signaling Pathway

Abstract

Aims: PGE₂ 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 PGE₂ on GABA_A receptor currents in rat cerebellar granule neurons. Methods: GABA_A currents were recorded using a patch-clamp technique. Cell surface and total protein of GABA_A β1/2/3 subunits was carried out by Western blot analysis. Results: Upon incubation of neurons with PGE₂ (1 µM) for 60 minutes, GABA_A currents were significantly potentiated. This PGE₂-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 PGE₂ did not increase the total expression level of GABA_A receptors, but significantly increased surface levels of GABA_A β1/2/3 subunits after 1 h of treatment. Consistently, both PKC and CaMKII inhibitors were able to reduce PGE₂-induced increases in cell surface expression of GABA_A receptors. Conclusion: Activation of either the PKC or CaMKII pathways by EP1 receptors mediates the PGE₂-induced increase in GABA_A currents. This suggests that upregulation of postsynaptic GABA_A receptors by PGE₂ may have profound effects on cerebellar functioning under physiological and pathological conditions.

The Consequences of Preterm Birth and Chorioamnionitis on Brainstem Respiratory Centers: Implications for Neurochemical Development and Altered Functions by Inflammation and Prostaglandins

“…Similar to pro-inflammatory cytokines, PGE 2 can alter neuronal excitability and neurotransmission. PGE 2 has been shown to both enhance and inhibit glutaminergic transmission, depress glycingeric signaling, and modulate GABAergic receptor expression, and although the exact mechanisms remain unclear, neuromodulation is thought to be dependent on the type of eicosanoid prostaglandin PGE2 receptors (EPRs) stimulated (Ahmadi et al, 2002 ; Chen and Bazan, 2005 ; Laaris and Weinreich, 2007 ; Marty et al, 2008 ; Lin et al, 2014 ; Yang et al, 2015 ).…”

Treatment with proteasome inhibitor bortezomib decreases organic anion transporting polypeptide (OATP) 1B3-mediated transport in a substrate-dependent manner

“…The supernatant was then resolved on 10% SDS-PAGE (Bio-Rad Laboratories, Inc., Hercules, CA, USA) and was subsequently immunoblotted with OATP1B3 (1:500 dilution) and Na-K-ATPase (1:8000 dilution; Abcam, Cambridge, MA, USA) antibodies. Na-K-ATPase was used as a loading control for surface protein levels of OATP1B3 [ 36 , 37 ]. The blots were also probed with a GAPDH antibody (1:1000 dilution, Santa Cruz, Dallas, TX, USA) to determine whether the surface fraction had intracellular protein contamination, similar to previously published.…”

Role of GABAAR in the Transition From Acute to Chronic Pain and the Analgesic Effect of Electroacupuncture on Hyperalgesic Priming Model Rats

“…Previous studies have demonstrated that changes in both GABAAR function and expression are involved in hyperalgesia (Ran et al, 2014;Obradovic et al, 2015). Especially, pervious reports indicated that PGE 2 can modify the GABA-activated current (Yang et al, 2015). So, we first to test whether PGE 2 or Car/PGE 2 injection would change the function of GABAAR activation from analgesia to hyperalgesia.…”