According to previous observations, the gene encoding the phosphatidylinositol-4-phosphate 5-kinase II alpha (PIP5K2A) is associated with schizophrenia. Specifically, the mutation ^N251SPIP5K2A has been discovered in schizophrenic partients but not in healthy individuals. Defective excitatory amino acid transporter EAAT3 has similarly been implicated in the development of schizophrenia. The present study thus explored, whether PIP5K2A is involved in the regulation of EAAT3 activity. EAAT3 has been expressed in Xenopus oocytes either without or with PIP5K2A and EAAT3 transporter activity estimated from glutamate (2 mM) induced current (I_glu) in dual voltage clamp experiments. In EAAT3 expressing oocytes, I_glu was enhanced by coexpression of wild type PIP5K2A. Coexpression of the schizophrenia associated mutant ^N251SPIP5K2A significantly decreased Iglu in both, oocytes expressing EAAT3 or both, EAAT3 and wild type PIP5K2A. Thus, ^N251SPIP5K2A exerts a dominant inhibitory effect. Injection of PI(4,5)P₂ increaseed I_glu in oocytes expressing EAAT3 alone, but not in oocytes expressing EAAT3 and PIP5K2A. The present observation discloses a novel mechanism of EAAT3 regulation, which may contribute to the deranged regulation of excitability in schizophrenic patients.