Haloperidol induces the nuclear translocation of phosphatidylinositol 3'-kinase to disrupt Akt phosphorylation in PC12 cells.

Publication Type:

Journal Article


J Psychiatry Neurosci, Volume 32, Issue 5, p.323-30 (2007)


Animals, Cloning, Molecular, DNA, Complementary, Haloperidol, PC12 Cells, Phosphatidylinositol 3-Kinases, Phosphorylation, Proto-Oncogene Proteins c-akt, Rats, Transfection, Translocation, Genetic


<p><b>OBJECTIVE: </b>The antipsychotic drug haloperidol (HAL) has been linked to apoptosis and to inhibition of prosurvival Akt signalling in pheochromocytoma (PC12) and neuronal cell cultures. However, the mechanism involved is unclear.</p><p><b>METHODS: </b>We used HAL to induce cytotoxicity in preneuronal PC12 cells. The expression and the subcellular localization of selected components of the PI3K-Akt survival cascade were monitored with standard biochemical approaches, such as subcellular fractionation, western blot analysis, gene transfer and fluorescence microscopy.</p><p><b>RESULTS: </b>PC12 cell stimulation with the epidermal growth factor (used as a control) results in normal processing of phosphatidylinositol 3'-kinase (PI3K)-Akt signalling (e.g., localization of PI3K to the plasma membrane and phosphorylation of Akt (Ser473). Surprisingly, HAL induces PI3K-generated phosphoinositol [phosphatidylinositol-3,4,5-triphosphate (PIP3), which conflicts with its ability to inhibit Akt. In fact, the production of PIP3s is nuclear, as assessed by the localized concentration of a fluorophore-tagged PIP3-targeting pleckstrin homology protein and a fluorophore-tagged substrate-trapping mutant of the phosphoinositide phosphatase, phosphatase and tensin homologue deleted on chromosome 10 (PTEN). However, phosphoinositide-dependent protein kinase 1 (PDK1, the activating kinase of Akt) does not colocalize to the nucleus with the PI3K complex. This effectively inactivates both cytoplasmic and nuclear pools of Akt.</p><p><b>CONCLUSION: </b>The differential compartmentalization of effectors of the PI3K-PDK1-Akt pathway is a unique means by which HAL disrupts Akt functioning in PC12 cells.</p>

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