Effects of inositol metabolism on lithium sensitivity and chemotaxis in Dictyostelium discoideum

Dictyostelium discoideum is a eukaryotic amoeba that has proven to be an excellent model system for the study of chemotaxis and development. Upon starvation, individual amoebae are able to aggregate and undergo development to form a fruiting body. Previously it has been demonstrated that this process is disrupted by two drugs commonly used to treat bipolar disorder, lithium and valproic acid (VPA) and in this study I show that this disruption is due to the inhibition of cell movement. Previous work has shown that ablation of the gene encoding prolyl oligopeptidase (PO) is able to confer resistance this effect. Both drugs have the common property of depleting intracellular inositol levels, and the observation that PO null cells have increased production of inositol 1,4,5 trisphosphate (Ins(1,4,5)P3) from the dephosphorylation of InsP5 therefore suggests that this activity may be responsible for lithium resistance. In this study I have cloned, and generated mutants of, the gene encoding this inositol phosphatase activity and shown that it is essential for lithium resistance in PO null cells and that this resistance is due to upregulated transcription of the lithium-sensitive IMPase family of genes. In addition I have shown that cells lacking phospholipase C activity are also lithium resistant, indicating that the recycling of inositol phosphates and lipids plays an important role in maintaining cell movement and lithium action