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)P3, 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)P3, an important signal molecule within the nervous system. As seen for Ins(1,4,5)P3 signalling, suppression of PtdIns(3,4,5)P3 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.
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October 2009
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Conference Article|
September 21 2009
PtdIns(3,4,5)P3 and inositol depletion as a cellular target of mood stabilizers
Regina Teo;
Regina Teo
*School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, U.K.
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Jason King;
Jason King
1
*School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, U.K.
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Emma Dalton;
Emma Dalton
*School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, U.K.
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Jonathan Ryves;
Jonathan Ryves
*School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, U.K.
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Robin S.B. Williams;
Robin S.B. Williams
†School of Biological Sciences, Royal Holloway, University of London, Egham, Surrey TW20 0EX, U.K.
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Adrian J. Harwood
Adrian J. Harwood
2
*School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, U.K.
2To whom correspondence should be addressed (email harwood.aj@cf.ac.uk).
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Publisher: Portland Press Ltd
Received:
June 16 2009
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem Soc Trans (2009) 37 (5): 1110–1114.
Article history
Received:
June 16 2009
Citation
Regina Teo, Jason King, Emma Dalton, Jonathan Ryves, Robin S.B. Williams, Adrian J. Harwood; PtdIns(3,4,5)P3 and inositol depletion as a cellular target of mood stabilizers. Biochem Soc Trans 1 October 2009; 37 (5): 1110–1114. doi: https://doi.org/10.1042/BST0371110
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