Disturbance of functioning of mutant associated with schizophrenia form PIP5K2A of kinase

Many schizophrenic patients are treated with anticholinergic agents that are known to modulate phosphoinositide metabolism. Not surprisingly, a number of genes involved in the synthesis or dephosphorylation of PI(4,5)P2 map very closely to regions of the genome that have been linked to schizophrenia. These include the phosphatidylinositol 3-kinases and PIP5K2A, a member of the phosphatidylinositol 4-phosphate 5-kinase family. Recently it has been found that the mutation (N251S)-PIP5K2A could be genetically linked to schizophrenia. Regulated by the product PIP2 of PIP5K2A are M-channels, voltage-gated K+ channels that regulate the excitability of many neurons. Neuronal Kv7.2/Kv7.3 and Kv7.3/Kv7.5 channels require PIP2 to open. Here, we study the effects of the neuronal PIP5K2A on KCNQ2, KCNQ5, KCNQ2/KCNQ3 and KCNQ3/KCNQ5 in the Xenopus expression system. We have found that wild type-PIP5K2A but not the schizophrenia associated mutant (N251S)-PIP5K2A activates heteromeric KCNQ2/KCNQ3 and KCNQ3/KCNQ5. Homomeric KCNQ2 and KCNQ5 channels were not activated by the kinase indicating that the presence of KCNQ3 in the channel complex is required for the kinase mediated effects. Thus, the insufficiency to stimulate PIP2 of (N251S)-PIP5K2A may contribute to the clinical phenotype of schizophrenia.