Molecular cloning of a novel isoform of diphosphoinositol polyphosphate phosphohydrolase: A potential target of lithium therapy

The mechanisms underlying the therapeutic effects of lithium are largely un known but may involve progressive adaptive alterations at the level of gene expression. Using differential display PCR, we identify a novel cDNA fragm ent, the expression of which was increased in the rat frontal cortex after 5 weeks of lithium administration. A full-length cDNA (2954-nt) was cloned by arrayed cDNA library screening, and sequencing of the clone revealed an open reading frame of 537-bp encoding a 179-residue protein. Amino acid seq uence comparisons revealed that our clone is a member of the Nudix hydrolas e family, with the highest percentage of homology (95%) being with a subtyp e of human diphosphoinositol polyphosphate phosphohydrolae, hDIPP2. Norther n blot analysis revealed that chronic lithium treatment significantly incre ased rDIPP2 mRNA levels in frontal cortex, but not in hippocampus, midbrain , and cerebellum. The effect of lithium on rDIPP2 mRNA expression was not s hared by two other anticonvulsant mood stabilizers, carbamazepine and valpr oate. Time-course studies showed that 1-week of lithium had no effect on rD IPP2 mRNA abundance in the frontal cortex. Our results suggest that DIPP2 m ay represent a biologically relevant target of lithium therapy, further sup porting the notion that abnormalities in inositol phosphate metabolism may be significant in the pathophysiology and pharmacotherapy of bipolar disord er. (C) 2001 American College of Neuropsychopharmacology. Published by Else vier Science Inc.