Fig. 2. Effects of lithium on the phosphoinositide cycle. In this scheme, occupancy of the receptor (R) by a specific agonist (A) initiates hydrolysis of PIP2 by PLC. Hydrolysis of PIP2 by PLC results in the formation of two major second messengers, IP3 and DAG. IP3 mobilizes calcium from intracellular stores, whereas DAG activates PKC (see text for details). IP3 is either dephosphorylated to form inositol 1,4-diphosphate (Ins 1,4,P2), inositol monophosphate (Ins P1), and, ultimately, free inositol, or phosphorylated to form inositol 1,3,4,5-tetraphosphate (Ins 1,3,4,5 P4), which is then dephosphorylated by sequential distinct pathways. Lithium, at therapeutically relevant concentrations, inhibits the dephosphorylation of inositol 1,3,4-triphosphate (Ins 1,3,4 P3), Ins 1,4,P2, and all three forms of inositol phosphatases (not shown in detail in the figure). Because the ability of a cell to maintain sufficient supplies of myoinositol is crucial to the resynthesis of the phosphoinositides, and because in most tissues inositol is derived primarily from recycling of inositol phosphates, one early consequence of lithium’s action is to reduce the levels of free inositol. As shown in the figure, inositol depletion can also perturb the DAG limb of the phosphoinositide turnover pathway. Thus, resynthesis of PI involves the transfer of the phosphatidic acidic moiety from cytidine diphosphate DAG to myoinositol. Presumably because of its effect of lowering levels of inositol, lithium treatment of a number of cells has been found to increase the levels of cytidine diphosphate DAG, and its interconvertible metabolite, DAG. Because DAG activates PKC, one consequence of lithium treatment is an activation of PKC. BBB = blood brain barrier.
