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Insulin‐like growth factor‐1‐dependent maintenance of neuronal metabolism through the phosphatidylinositol 3‐kinase–Akt pathway is inhibited by C 2 ‐ceramide in CAD cells
Ist Teil von
The European journal of neuroscience, 2007-05, Vol.25 (10), p.3030-3038
Erscheinungsjahr
2007
Link zum Volltext
Quelle
Psychology and Behavioral Sciences Collection
Beschreibungen/Notizen
Abstract Ceramide is a lipid second‐messenger generated in response to stimuli associated with neurodegeneration that induces apoptosis, a mechanism underlying neuronal death in Parkinson's disease. We tested the hypothesis that insulin‐like growth factor‐1 (IGF‐1) could mediate a metabolic response in CAD cells, a dopaminergic cell line of mesencephalic origin that differentiate into a neuronal‐like phenotype upon serum removal, extend processes resembling neurites, synthesize abundant dopamine and noradrenaline and express the catecholaminergic biosynthetic enzymes tyrosine hydroxylase and dopamine β‐hydroxylase, and that this process was phosphatidylinositol 3‐kinase (PI 3‐K)–Akt‐dependent and could be inhibited by C 2 ‐ceramide. The metabolic response was evaluated as real‐time changes in extracellular acidification rate (ECAR) using microphysiometry. The IGF‐1‐induced ECAR response was associated with increased glycolysis, determined by increased NAD(P)H reduction, elevated hexokinase activity and Akt phosphorylation. C 2 ‐ceramide inhibited all these changes in a dose‐dependent manner, and was specific, as it was not induced by the inactive C 2 ‐ceramide analogue C 2 ‐dihydroceramide. Inhibition of the upstream kinase, PI 3‐K, also inhibited Akt phosphorylation and the metabolic response to IGF‐1, similar to C 2 ‐ceramide. Decreased mitochondrial membrane potential occurred after loss of Akt phosphorylation. These results show that IGF‐1 can rapidly modulate neuronal metabolism through PI 3‐K–Akt and that early metabolic inhibition induced by C 2 ‐ceramide involves blockade of the PI 3‐K–Akt pathway, and may compromise the first step of glycolysis. This may represent a new early event in the C 2 ‐ceramide‐induced cell death pathway that could coordinate subsequent changes in mitochondria and commitment of neurons to apoptosis.