Genetic control of lithium sensitivity and regulation of inositol biosynthetic genes.

Lithium (Li(+)) is a common treatment for bipolar mood disorder, a major psychiatric illness with a lifetime prevalence of more than 1%. Risk of bipolar disorder is heavily influenced by genetic predisposition, but is a complex genetic trait and, to date, genetic studies have provided little insight into its molecular origins. An alternative approach is to investigate the genetics of Li(+) sensitivity.

Glycogen synthase kinase-3 is required for efficient Dictyostelium chemotaxis.

Glycogen synthase kinase-3 (GSK3) is a highly conserved protein kinase that is involved in several important cell signaling pathways and is associated with a range of medical conditions. Previous studies indicated a major role of the Dictyostelium homologue of GSK3 (gskA) in cell fate determination during morphogenesis of the fruiting body; however, transcriptomic and proteomic studies have suggested that GSK3 regulates gene expression much earlier during Dictyostelium development. To investigate a potential earlier role of GskA, we examined the effects of loss of gskA on cell aggregation.

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.

A systematic investigation of the protein kinases involved in NMDA receptor-dependent LTD: evidence for a role of GSK-3 but not other serine/threonine kinases.

Background: The signalling mechanisms involved in the induction of N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression (LTD) in the hippocampus are poorly understood. Numerous studies have presented evidence both for and against a variety of second messengers systems being involved in LTD induction. Here we provide the first systematic investigation of the involvement of serine/threonine (ser/thr) protein kinases in NMDAR-LTD, using whole-cell recordings from CA1 pyramidal neurons.

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

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.

Use of a penetratin-linked peptide in Dictyostelium.

The plasma membrane is an effective barrier to most macromolecules and hydrophilic molecules. Remarkably, a class of positively charged cell-penetrating peptides (CPPs) has been discovered that can translocate themselves and associated cargoes into the cytoplasm. These have been used to carry oligopeptide- and oligonucleotide-based inhibitors into mammalian cells.

GSK-3 activity in neocortical cells is inhibited by lithium but not carbamazepine or valproic acid.

Objectives: Lithium (Li(+)) has been suggested to target the enzyme glycogen synthase kinase 3 (GSK-3) as a mechanism of mood stabilization. Inhibition of GSK-3 by a second mood-stabilizer, valproic acid (VPA), has also been reported, but this effect is dependent on cell type. It is currently unknown if carbamazepine (CBZ) inhibits GSK-3 activity.

Dd-Alix, a conserved endosome-associated protein, controls Dictyostelium development.

We have characterized the Dictyostelium homolog of the mammalian protein Alix. Dd-Alix is encoded by a single gene and is expressed during vegetative growth and multicellular development. We showed that the alx null strain fails to complete its developmental program.

The interaction of glycogen synthase kinase-3 (GSK-3) with the cell cycle.

GSK-3 is a multifunctional protein kinase known to play a pivotal role in the regulation of metabolism, the cytoskeleton and gene expression. It also interacts with the cell cycle in a number of ways. GSK-3 forms part of both Wnt and Hh signalling pathways and hence controls expression of a number of cell cycle regulatory genes.

Glycogen synthase kinase-3 inhibition by lithium and beryllium suggests the presence of two magnesium binding sites.

Lithium inhibits (Li(+)) glycogen synthase kinase-3 (GSK-3) by competition for magnesium (Mg(2+)), but not ATP or substrate. Here, we show that the group II metal ion beryllium (Be(2+)) is a potent inhibitor of GSK-3 and competes for both Mg(2+) and ATP. Be(2+) also inhibits the related protein kinase cdc2 at similar potency, but not MAP kinase 2.

Identification of the Axin and Frat binding region of glycogen synthase kinase-3.

Glycogen synthase kinase-3 (GSK-3) is a key component of several signaling pathways including those regulated by Wnt and insulin ligands. Specificity in GSK-3 signaling is thought to involve interactions with scaffold proteins that localize GSK-3 regulators and substrates. This report shows that GSK-3 forms a low affinity homodimer that is disrupted by binding to Axin and Frat.