Abstract
ABSTRACTValproic acid (VPA) provides a common treatment for both epilepsy and bipolar disorder; however, common cellular mechanisms relating to both disorders have yet to be proposed. Here, we explore the possibility of a diacylglycerol kinase (DGK) playing a role in regulating the effect of VPA relating to the treatment of both disorders, using the biomedical model Dictyostelium discoideum. DGK enzymes provide the first step in the phosphoinositide recycling pathway, implicated in seizure activity. They also regulate levels of diacylglycerol (DAG), thereby regulating the protein kinase C (PKC) activity that is linked to bipolar disorder-related signalling. Here, we show that ablation of the single Dictyostelium dgkA gene results in reduced sensitivity to the acute effects of VPA on cell behaviour. Loss of dgkA also provides reduced sensitivity to VPA in extended exposure during development. To differentiate a potential role for this DGKA-dependent mechanism in epilepsy and bipolar disorder treatment, we further show that the dgkA null mutant is resistant to the developmental effects of a range of structurally distinct branched medium-chain fatty acids with seizure control activity and to the bipolar disorder treatment lithium. Finally, we show that VPA, lithium and novel epilepsy treatments function through DAG regulation, and the presence of DGKA is necessary for compound-specific increases in DAG levels following treatment. Thus, these experiments suggest that, in Dictyostelium, loss of DGKA attenuates a common cellular effect of VPA relating to both epilepsy and bipolar disorder treatments, and that a range of new compounds with this effect should be investigated as alternative therapeutic agents.This article has an associated First Person interview with the first author of the paper.
Highlights
Dictyostelium DGKA represents the origins of the family of mammalian diacylglycerol kinase (DGK) enzymes Because DGKs catalyse the first step in the DAG salvage pathway (Fig. 1A), we initially investigated homology between the single Dictyostelium DGKA protein and the ten members of the mammalian DGK family of enzymes (Fig. 1B-F)
We employed the simple biomedical model system Dictyostelium to investigate the cellular mechanisms of the epilepsy and bipolar disorder treatment, Valproic acid (VPA), through the key enzyme, DGKA, which is responsible for the phosphorylation of DAG to PA
We show that loss of the Dictyostelium dgkA gene significantly reduced sensitivity to the acute effects of VPA on changes in cell behaviour and in multicellular development, suggesting that the effect of VPA on cellular function is at least partially dependent upon DGKA in Dictyostelium
Summary
Diacylglycerol kinases (DGKs) provide the first step in the phosphoinositide salvage pathway, functioning in the phosphorylation of diacylglycerol (DAG) to produce phosphatidic. Owing to the numerous roles of DAG, and the ten DGK isoforms in humans, few studies have considered a role for DGK-dependent signalling in disease states. The exceptions to this are several knockout studies that have linked various DGK isoforms with epilepsy [DGKβ (Ishisaka et al, 2103), DGKδ (Leach et al, 2007) and DGKε (Rodriguez de Turco et al, 2001)] and bipolar disorder [DGKβ (Kakefuda et al, 2010; Squassina et al, 2009) and DGKη (Baum et al, 2007; Moya et al, 2010)]. No studies, to our knowledge, have investigated DGK-dependent signalling as an overlapping process relating to both epilepsy and bipolar disorder treatment
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