title: The mood stabiliser lithium suppresses PIP3 signalling in Dictyostelium and human cells.
abstract: 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 [IP(3), also known as Ins(1,4,5)P(3)] 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 [PIP(3), also known as PtdIns(3,4,5)P(3)] 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 PIP(3)-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 PIP(3) signalling.
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff, UK.
authors.forename: Jason S
authors.initials: JS
authors.lastname: King
authors.forename: Regina
authors.initials: R
authors.lastname: Teo
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ryves
authors.forename: Jonathan V
authors.initials: JV
authors.lastname: Reddy
authors.forename: Owen
authors.initials: O
authors.lastname: Peters
authors.forename: Ben
authors.initials: B
authors.lastname: Orabi
authors.forename: Oliver
authors.initials: O
authors.lastname: Hoeller
authors.forename: Robin S B
authors.initials: RS
authors.lastname: Williams
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Harwood
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D004023:Dictyostelium / Q000166:cytology* / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D008094:Lithium / Q000494:pharmacology*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D018692:Antimanic Agents; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D008094:Lithium