PGE2 glycerol ester, a COX-2 oxidative metabolite of 2-arachidonoyl glycerol, modulates inhibitory synaptic transmission in mouse hippocampal neurons.
The oxygenation of endogenous cannabinoids (eCBs) 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide by cyclooxygenase-2 (COX-2) produces novel types of prostanoids: prostaglandin glycerol esters (PG-Gs) and prostaglandin ethanolamides (PG-EAs). However, the physiological function of COX-2 oxidative metabolites of eCBs is still unclear. Here we demonstrate that PGE2-G, a COX-2 oxidative metabolite of 2-AG, induced a concentration-dependent increase in the frequency ofminiature inhibitory postsynaptic currents (mIPSCs) in primary cultured hippocampal neurons, an effect opposite to that of 2-AG. This increase was not inhibited by SR141716, a CB1 receptor antagonist, but was attenuated by an IP3 or MAPK inhibitor. In addition, we also examined the effects of other prostanoids derived from COX-2 oxygenation of eCBs on mIPSCs. PGD2-G, PGF2alpha-G and PGD2-EA, but not PGE2-EA or PGF2alpha-EA, also increased the frequency of mIPSCs. The eCB-derived prostanoid-induced responses appeared to be different from those of corresponding arachidonic acid-derived prostanoids, implying that these effects are not mediated via known prostanoid receptors. We further discovered that the inhibition of COX-2 activity reduced inhibitory synaptic activity and augmented depolarization-induced suppression of inhibition (DSI), whereas the enhancement of COX-2 augmented the synaptic transmission and abolished DSI. Our results, which show that COX-2 oxidative metabolites of eCBs exert opposite effects to their parent molecules on inhibitory synaptic transmission, suggest that alterations in COX-2 activity will have significant impact on endocannabinoid signalling in hippocampal synaptic activity.
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Nan
N
Sang
Jian
J
Zhang
Chu
C
Chen
D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000378:metabolism*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004952:Esters / Q000008:administration & dosage; D005989:Glycerides / Q000378:metabolism*; D005990:Glycerol / Q000008:administration & dosage; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010084:Oxidation-Reduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D001095:Arachidonic Acids; D063388:Endocannabinoids; D004952:Esters; D005989:Glycerides; C094503:glyceryl 2-arachidonate; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D005990:Glycerol