Possible role of 3′(2′)-phosphoadenosine-5′-phosphate phosphatase in the etiology and therapy of bipolar disorder

Bipolar affective disorder (BPD) is a multifactorial, severe, chronic and disabling illness with 50% heritability that affects 1-2% of the population. Lithium ions (Li) are the drug of choice for BPD. Yet, 20-40% of patients fail to respond to Li. Although numerous biochemical and cellular effects have been attributed to Li, its therapeutic mechanism of action has not been elucidated. This review presents the possible involvement of 3'(2')-phosphoadenosine-5'-phosphate (PAP) phosphatase in the etiology of bipolar disorder and the mechanism of action of Li. Of the enzymes inhibited by Li, PAP phosphatase is inhibited with the lowest Ki (0.3 mM). At therapeutic concentrations of Li (0.5-1.5 mM), inhibition is greater than 80%. Therefore, PAP phosphatase is a strong candidate for Li's therapeutic mechanism of action. In yeast, a PAP phosphatase knockout mutation leads to the accumulation of PAP, which affects ribosomal-, transfer- and small nucleolar-RNA processing. PAP accumulation in the mammalian brain following Li inhibition of PAP phosphatase may very well account for the observed effects of Li on gene expression and behavior. Furthermore, we have reported significant changes in PAP phosphatase levels in postmortem frontal cortex of bipolar patients.