Activation of EP2 prostanoid receptors in human glial cell lines stimulates the secretion of BDNF.
Prostaglandin E(2) (PGE(2)) is produced at high levels in the injured central nervous system, where it is generally considered a cytotoxic mediator of inflammation. The cellular actions of PGE(2) are mediated by G-protein signaling activated by prostanoid receptors termed EP(1), EP(2), EP(3) and EP(4). Recent studies have implicated the EP(2) prostanoid receptor to be in apparently conflicting roles promoting neuronal death in some model systems and the survival of neurons in others. Here we show that treatment of immortalized human microglia and CCF-STTG1 astrocytes with either PGE(2) or the EP(2) selective agonist butaprost stimulates the release of brain-derived neurotrophic factor (BDNF). Both cell lines express mRNA for the EP(2) receptor, whereas transcripts for the other subtypes are not detected. Pharmacological studies using PGE(2) and modulators of cyclic AMP signaling implicate this pathway in PGE(2)-stimulated BDNF release. These results indicate that EP(2) prostanoid receptor activation induces BDNF secretion through stimulation of cyclic AMP dependent signaling. Our findings provide a mechanism by which endogenous PGE(2) might contribute to either neurotoxicity or neuroprotection in the injured brain via the induction of BDNF release from microglial cells and astrocytes.
Program in Neuroscience, The University of Arizona, College of Pharmacy, Gould-Simpson 611, PO Box 210077, Tucson, AZ 85721, USA.
Anthony J
AJ
Hutchinson
Chih-Ling
CL
Chou
Davelene D
DD
Israel
Wei
W
Xu
John W
JW
Regan
D000262:Adenylyl Cyclases / Q000378:metabolism; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008156:Luciferases / Q000235:genetics; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D014162:Transfection
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D000242:Cyclic AMP; D008156:Luciferases; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D000527:Alprostadil; C048491:butaprost; D015232:Dinoprostone