Prostaglandin synthesis in rat brain astrocytes is under the control of the n-3 docosahexaenoic acid, released by group VIB calcium-independent phospholipase A2.
In the current study, we reveal that in astrocytes the VIB Ca(2+)-independent phospholipase A(2) is the enzyme responsible for the release of docosahexaenoic acid (22:6n-3). After pharmacological inhibition and siRNA silencing of VIB Ca(2+)-independent phospholipase A(2), docosahexaenoic acid release was strongly suppressed in astrocytes, which were acutely stimulated (30 min) with ATP and glutamate or after prolonged (6 h) stimulation with the endotoxin lipopolysaccharide. Docosahexaenoic acid release proceeds simultaneously with arachidonic acid (20:4n-6) release and prostaglandin liberation from astrocytes. We found that prostaglandin production is negatively controlled by endogenous docosahexaenoic acid, since pharmacological inhibition and siRNA silencing of VIB Ca(2+)-independent phospholipase A(2) significantly amplified the prostaglandin release by astrocytes stimulated with ATP, glutamate, and lipopolysaccharide. Addition of exogenous docosahexaenoic acid inhibited prostaglandin synthesis, which suggests that the negative control of prostaglandin synthesis observed here is likely due to competitive inhibition of cyclooxygenase-1/2 by free docosahexaenoic acid. Additionally, treatment of astrocytes with docosahexaenoic acid leads to the reduction in cyclooxygenase-1 expression, which also contributes to reduced prostaglandin production observed in lipopolysaccharide-stimulated cells. Thus, we identify a regulatory mechanism important for the brain, in which docosahexaenoic acid released from astrocytes by VIB Ca(2+)-independent phospholipase A(2) negatively controls prostaglandin production.
Strokin
Mikhail
M
Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, Leipziger Straße, Magdeburg, GermanyBelozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia.
Sergeeva
Marina
M
Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, Leipziger Straße, Magdeburg, GermanyBelozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia.
Reiser
Georg
G
Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, Leipziger Straße, Magdeburg, GermanyBelozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia.
D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D054522:Group VI Phospholipases A2; D008070:Lipopolysaccharides / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D011453:Prostaglandins / Q000096:biosynthesis*; D034622:RNA Interference; D051381:Rats
D004791:Enzyme Inhibitors; D015525:Fatty Acids, Omega-3; D008070:Lipopolysaccharides; D011453:Prostaglandins; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054522:Group VI Phospholipases A2; D054467:Phospholipases A2; D002118:Calcium