Effects of hypoxia on oligodendrocyte signal transduction.
We have previously established that 21-day-old postnatal rat oligodendrocytes, maintained in monolayer culture and subjected to 6 h of hypoxia, show reversible inhibition of synthesis of alpha-hydroxy fatty acid and myelin basic protein but a dramatic induction of a 22-kDa protein, suggesting that this is a good model to study the mechanism of CNS demyelination caused by hypoxic injury. We now report that hypoxia also dramatically inhibits the basal protein kinase C-mediated phosphorylation of myelin basic protein and myelin 2',3'-cyclic nucleotide phosphohydrolase by 80%, but that the inhibition of phosphorylation can be reversed by addition of a protein kinase C activator, phorbol 12-myristate 13-acetate. The mechanism of action appears to involve the uncoupling of signal transduction at a site before phospholipase C, because hypoxia did not affect protein kinase C activity or its translocation to the membrane fraction. The most potent activator of phospholipase C (as measured by inositol phosphate release) was carbachol (muscarinic M1 receptor agonist), followed by L-phenylephrine (alpha 1-adrenergic receptor agonist) in normal oligodendrocytes. Excitatory amino acids and histamine were ineffective. Hypoxia for 6 h completely inhibited both muscarinic and alpha 1-adrenergic receptor-mediated inositol monophosphate release but did not affect phospholipase D-coupled phosphatidylethanol production in response to carbachol. We therefore conclude from this and earlier work that early, reversible changes in oligodendrocyte metabolism result not simply from ATP depletion, but may specifically target GTP binding protein-mediated processes.
Qi
Y
Y
Department of Pediatrics, Joseph P. Kennedy Jr. Mental Retardation Research Center, University of Chicago, Illinois 60637.
Dawson
G
G
D000818:Animals; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D007295:Inositol Phosphates / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D009836:Oligodendroglia / Q000502:physiology*; D009840:Oligomycins / Q000494:pharmacology; D010739:Phospholipase D / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D007295:Inositol Phosphates; D004676:Myelin Basic Protein; D009840:Oligomycins; D011506:Proteins; C002647:inositol 1-phosphate; D011493:Protein Kinase C; D010739:Phospholipase D