Molecular cloning of a novel isoform of diphosphoinositol polyphosphate phosphohydrolase: a potential target of
1Section of Biochemical Psychiatry, Centre for Addiction and Mental Health, Clarke Site, Toronto, Ontario, Canada.
Abstract:
The mechanisms underlying the therapeutic effects of lithium are largely unknown but may involve progressive adaptive alterations at the level of gene expression. Using differential display PCR, we identify a novel cDNA fragment, 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 sequence comparisons revealed that our clone is a member of the Nudix hydrolase family, with the highest percentage of homology (95%) being with a subtype of human diphosphoinositol polyphosphate phosphohydrolase, hDIPP2. Northern blot analysis revealed that chronic lithium treatment significantly increased rDIPP2 mRNA levels in frontal cortex, but not in hippocampus, midbrain, and cerebellum. The effect of lithium on rDIPP2 mRNA expression was not shared by two other anticonvulsant mood stabilizers, carbamazepine and valproate. Time-course studies showed that 1-week of lithium had no effect on rDIPP2 mRNA abundance in the frontal cortex. Our results suggest that DIPP2 may represent a biologically relevant target of lithium therapy, further supporting the notion that abnormalities in inositol phosphate metabolism may be significant in the pathophysiology and pharmacotherapy of bipolar disorder.
Insights
Lithium therapy may work by altering gene expression. Researchers found lithium increases diphosphoinositol polyphosphate phosphohydrolase 2 (DIPP2) mRNA in rat brains, suggesting DIPP2 is a key target.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- The therapeutic mechanisms of lithium, a mood stabilizer, remain largely unknown.
- Gene expression alterations are hypothesized to underlie lithium's effects.
- Inositol phosphate metabolism is implicated in bipolar disorder pathophysiology.
Purpose of the Study:
- To identify novel genes regulated by lithium in the rat frontal cortex.
- To investigate the role of diphosphoinositol polyphosphate phosphohydrolase 2 (DIPP2) in lithium's therapeutic effects.
- To explore the significance of inositol phosphate metabolism in bipolar disorder pharmacotherapy.
Main Methods:
- Differential display PCR was used to identify differentially expressed genes.
- Full-length cDNA cloning and sequencing were performed.
- Northern blot analysis and time-course studies assessed mRNA levels in various brain regions.
Main Results:
- A novel cDNA fragment, identified as rat diphosphoinositol polyphosphate phosphohydrolase 2 (rDIPP2), showed increased expression in the frontal cortex after chronic lithium treatment.
- Lithium significantly elevated rDIPP2 mRNA levels in the frontal cortex, but not other brain regions.
- This effect was specific to lithium and not observed with carbamazepine or valproate.
Conclusions:
- DIPP2 represents a potential biologically relevant target for lithium therapy.
- These findings support the hypothesis that inositol phosphate metabolism plays a significant role in bipolar disorder.
- Further research into DIPP2 and inositol metabolism could advance bipolar disorder treatment.
