PtdIns(3,4,5)P(3) and inositol depletion as a cellular target of mood stabilizers.
Lithium (Li(+)) is the mood stabilizer most frequently used in the treatment of bipolar mood disorder; however, its therapeutic mechanism is unknown. In the 1980s, Berridge and colleagues proposed that Li(+) treatment acts via inhibition of IMPase (inositol monophosphatase) to deplete the cellular concentration of myo-inositol. Inositol depletion is also seen with the alternative mood stabilizers VPA (valproic acid) and CBZ (carbamazepine), suggesting a common therapeutic action. All three drugs cause changes in neuronal cell morphology and cell chemotaxis; however, it is unclear how reduced cellular inositol modulates these changes in cell behaviour. It is often assumed that reduced inositol suppresses Ins(1,4,5)P(3), a major intracellular signal molecule, but there are other important phosphoinostide-based signal molecules in the cell. In the present paper, we discuss evidence that Li(+) has a substantial effect on PtdIns(3,4,5)P(3), an important signal molecule within the nervous system. As seen for Ins(1,4,5)P(3) signalling, suppression of PtdIns(3,4,5)P(3) signalling also occurs via an inositol-depletion mechanism. This has implications for the cellular mechanisms controlling phosphoinositide signalling, and offers insight into the genetics underlying risk of bipolar mood disorder.
Teo
Regina
R
School of Biosciences, Cardiff University, Museum Avenue, Cardiff, UK.
King
Jason
J
Dalton
Emma
E
Ryves
Jonathan
J
Williams
Robin S B
RS
Harwood
Adrian J
AJ
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D002220:Carbamazepine / Q000494:pharmacology / Q000627:therapeutic use; D002633:Chemotaxis / Q000187:drug effects; D006801:Humans; D007294:Inositol / Q000378:metabolism*; D018020:Lithium Compounds / Q000494:pharmacology / Q000627:therapeutic use; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
D018692:Antimanic Agents; D018020:Lithium Compounds; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D002220:Carbamazepine; D007294:Inositol; D014635:Valproic Acid