Loss of a prolyl oligopeptidase confers resistance to lithium by elevationof inositol (1,4,5) trisphosphate

The therapeutic properties of lithium ions (Li+) are well known; however, t he mechanism of their action remains unclear. To investigate this problem, we have isolated Li+-resistant mutants from Dictyostelium, Here, we describ e the analysis of one of these mutants. This mutant lacks the Dictyostelium prolyl oligopeptidase gene (dpoA), We have examined the relationship betwe en dpoA and the two major biological targets of lithium: glycogen synthase kinase 3 (GSK-3) and signal transduction via inositol (1,4,5) trisphosphate (IP3), We find no evidence for an interaction with GSK-3, but instead find that loss of dpoA causes an increased concentration of IP3, The same incre ase in IP3 is induced in wild-type cells by a prolyl oligopeptidase (POase) inhibitor. IP3 concentrations increase via an unconventional mechanism tha t involves enhanced dephosphorylation of inositol (1,3,4,5,6) pentakisphosp hate, Loss of DpoA activity therefore counteracts the reduction in IP3 conc entration caused by Li+ treatment. Abnormal POase activity is associated wi th both unipolar and bipolar depression; however, the function of POase in these conditions is unclear. Our results offer a novel mechanism that links POase activity to IP3 signalling and provides further clues for the action of Li+ in the treatment of depression.