MOLECULAR EFFECTS of lithium

Glycogen synthase kinase-3 (GSK-3) and inositol monophosphatase (IMPase) are direct targets of lithium. This simplified figure highlights relevant interactions among intracellular pathways related to lithium’s action. GSK-3 functions as an intermediary in a number of signaling pathways including neurotrophic signaling pathways, the insulin–phosphatidylinositol 3 kinase (PI3K) pathway and the Wnt pathway—activation of these pathways inhibits GSK-3. The upper left portion of the figure depicts lithium’s actions on the PI signaling pathway. Activation of some G proteins induces phopsholipase C hydrolysis of phosphoinositide-4,5-bisphosphate (PIP₂) to diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP₃). DAG activates protein kinase C (PKC). IP₃ binds to the IP₃ receptor that also functions as a calcium channel in the cell. IP₃ is recycled back to PIP₂ by IMPase and inositol polyphosphatase phosphatase (IPPase); both of which are inhibited by lithium (21). The inositol depletion hypothesis suggests that lithium exerts its therapeutic actions by depleting free inositol and thus dampening the activation of downstream signaling pathways in neurons (28). Modified and reproduced with permission from (154)