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The mood stabiliser lithium suppresses PIP3 signalling in 'Dictyostelium' and human cells

King, Jason, Teo, Regina, Ryves, William Jonathan, Reddy, Jonathan Venkat, Peters, Owen Morgan ORCID:, Orabi, Ben, Hoeller, Oliver, Williams, Robin S. B. and Harwood, Adrian John ORCID: 2009. The mood stabiliser lithium suppresses PIP3 signalling in 'Dictyostelium' and human cells. Disease Models & Mechanisms 2 (5-6) , pp. 306-312. 10.1242/dmm.001271

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Bipolar mood disorder (manic depression) is a major psychiatric disorder whose molecular origins are unknown. Mood stabilisers offer patients both acute and prophylactic treatment, and experimentally, they provide a means to probe the underlying biology of the disorder. Lithium and other mood stabilisers deplete intracellular inositol and it has been proposed that bipolar mood disorder arises from aberrant inositol (1,4,5)-trisphosphate [IP3, also known as Ins(1,4,5)P3] signalling. However, there is no definitive evidence to support this or any other proposed target; a problem exacerbated by a lack of good cellular models. Phosphatidylinositol (3,4,5)-trisphosphate [PIP3, also known as PtdIns(3,4,5)P3] is a prominent intracellular signal molecule within the central nervous system (CNS) that regulates neuronal survival, connectivity and synaptic function. By using the genetically tractable organism Dictyostelium, we show that lithium suppresses PIP3-mediated signalling. These effects extend to the human neutrophil cell line HL60. Mechanistically, we show that lithium attenuates phosphoinositide synthesis and that its effects can be reversed by overexpression of inositol monophosphatase (IMPase), consistent with the inositol-depletion hypothesis. These results demonstrate a lithium target that is compatible with our current knowledge of the genetic predisposition for bipolar disorder. They also suggest that lithium therapy might be beneficial for other diseases caused by elevated PIP3 signalling.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: Q Science > QR Microbiology
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
R Medicine > RM Therapeutics. Pharmacology
Publisher: The Company of Biologists Ltd
ISSN: 1754-8403
Last Modified: 02 Dec 2022 11:55

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