Molecular pharmacology in a simple model system: Implicating MAP kinase and phosphoinositide signalling in bipolar disorder

Abstract

Understanding the mechanisms of drug action has been the primary focus for pharmacological researchers, traditionally using rodent models. However, non-sentient model systems are now increasingly being used as an alternative approach to better understand drug action or targets. One of these model systems, the social amoeba Dictyostelium, enables the rapid ablation or over-expression of genes, and the subsequent use of isogenic cell culture for the analysis of cell signalling pathways in pharmacological research. The model also supports an increasingly important ethical view of research, involving the reduction, replacement and refinement of animals in biomedical research. This review outlines the use of Dictyostelium in understanding the pharmacological action of two commonly used bipolar disorder treatments (valproic acid and lithium). Both of these compounds regulate mitogen activated protein (MAP) kinase and inositol phospholipid-based signalling by unknown means. Analysis of the molecular pathways targeted by these drugs in Dictyostelium and translation of discoveries to animal systems has helped to further understand the molecular mechanisms of these bipolar disorder treatments.

Nhe1 Is Essential for Potassium but Not Calcium Facilitation of Cell Motility and the Monovalent Cation Requirement for Chemotactic Orientation in Dictyostelium discoideum

“…In Dictyostelium discoideum, which serves as a powerful model for studying animal cell motility (4,6,20,34,41,42,43,45,50,82,87,86,92,98), either extracellular K ϩ or Ca 2ϩ at an optimum concentration of 40 mM or 20 mM, respectively, enhances most aspects of basic cell motility in the absence of chemoattractant, including cell elongation, uropod formation, the suppression of lateral pseudopod formation, velocity, directional persistence, and localization of myosin II in the posterior cell cortex (51,78). These facilitating concentrations of K ϩ or Ca 2ϩ cannot be replaced with other monovalent or divalent cations (51) and are within the range of the soluble concentrations of the two cations found in soil (1,5,32,44,49,56) and manure (9,66,83), two common niches in which soil amoebae thrive (12,27,35,67,71).…”

An ancestral non-proteolytic role for presenilin proteins in multicellular development of the social amoeba Dictyostelium discoideum

“…However, the social amoeba Dictyostelium discoideum is the simplest model organism that possesses two presenilin proteins as well as the other three components of the c-secretase complex (Boeckeler and Williams, 2007;McMains et al, 2010). Dictyostelium has been extensively used in a range of motility (Janetopoulos and Firtel, 2008), developmental (Loomis and Shaulsky, 2011) and biomedical studies (Chang et al, 2012;Francione and Fisher, 2011;Ludtmann et al, 2011;Myre et al, 2011;Terbach et al, 2011), and has a number of experimental advantages over existing models (Williams et al, 2006). In this study, we employ the advantages of Dictyostelium to explore the role of the human presenilin 1 protein (PSEN1) in development.…”

The antiepileptic drug valproic acid and other medium-chain fatty acids acutely reduce phosphoinositide levels independently of inositol in Dictyostelium

“…We have employed Dictyostelium to understand the molecular mechanisms underlying VPA action in regards to both putative bipolar-disorder- and epilepsy-related signalling effects (Boeckeler et al, 2006; Eickholt et al, 2005; Williams et al, 1999; Williams et al, 2002; Xu et al, 2007; Ludtmann et al, 2011), and to study the mechanisms of uptake (Terbach et al, 2011). Our previous work has shown that, in Dictyostelium , both VPA and a structurally unrelated bipolar disorder treatment, lithium, chronically reduce the levels of inositol phosphate {e.g.…”