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

Gonzalo Arboleda, Tze Jen Huang, Catherine Waters, Alex Verkhratsky, Paul Fernyhough, Rosemary M. Gibson

    Research output: Contribution to journalArticle

    59 Citations (Scopus)

    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 C2-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 C2-ceramide analogue C2-dihydroceramide. Inhibition of the upstream kinase, PI 3-K, also inhibited Akt phosphorylation and the metabolic response to IGF-1, similar to C2-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 C2-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 C2-ceramide-induced cell death pathway that could coordinate subsequent changes in mitochondria and commitment of neurons to apoptosis.

    Original languageEnglish
    Pages (from-to)3030-3038
    Number of pages9
    JournalEuropean Journal of Neuroscience
    Volume25
    Issue number10
    DOIs
    Publication statusPublished - May 2007

    Keywords

    • Apoptosis
    • Glycolysis
    • Hexokinase
    • Mitochondria

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