Activation of phosphoinositide 3-kinase delta by antipsychotic drugs: Preliminary results

Abstract

Background: Catalytic subunit delta of phosphoinositide 3-kinase, p110δ, encoded by the PIK3CD gene, was recently proposed as a target for pharmacological treatment of schizophrenia. Current antipsychotic drugs were found to decrease the mRNA expression of PIK3CD, but the mechanism of this process is not known. The aim of the study was to elucidate the mechanism by which antipsychotic drugs affect the mRNA expression of PIK3CD.

Methods: The direct effect of haloperidol, clozapine, olanzapine, quetiapine and amisulpride on p110δ enzymatic activity was tested with a kinase assay, and the results were referenced against data on the mRNA expression of PIK3CD.

Results: Haloperidol, clozapine, olanzapine and quetiapine, but not amisulpride, at the concentration of 20-80 μM, were found to significantly increase enzymatic activity of p110δ by up to two times in a dose-dependent manner. Linear regression analysis revealed that more than 40% of the variance in antipsychotic drugs-induced changes in the expression of PIK3CD mRNA was explained only by changes in antipsychotic drug-regulated p110δ enzymatic activity (p = 0.011).

Conclusions: Antipsychotic drugs differentially increase the enzymatic activity of p110δ. This effect is associated with that of mRNA expression of the PIK3CD gene. Drug-enzyme interaction may explain the effect of antipsychotic drugs on the expression of PIK3CD mRNA, however, further studies are needed to investigate this hypothesis.

Keywords: Antipsychotic drugs; Kinase assay; Mechanism of action; Phosphoinositide 3-kinase delta; Schizophrenia.