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Figure S4. Aspects of the inositol cycle pertinent to lithium. (A) Lithium inhibits inositol monophosphatase (IMPase) to reduce free inositol that decreases intracellular inositol-1,4,5-triphosphate (IP3) levels (Berridge et al., 1989; Coyle and Duman, 2003), leading to enhanced clearance of mutant proteins through autophagy by a rundown of the inositol cycle (green arrows). Addition of inositol in the form of myo-inositol and inhibitor of prolyl oligopeptidase activity called prolyl endopeptidase inhibitor 2 (PEI) increase the levels of intracellular IP3 (Williams et al., 1999, 2002) and thereby lead to a decrease in the clearance of mutant proteins by autophagy (red arrows). Therefore, myo-inositol and PEI should reverse or abolish the protective effect of lithium on clearance. (B) Intracellular inositol-1,4,5-triphosphate (IP3) levels were measured in COS-7 cells treated with 10 mM LiCl for 0 min, 1 min, 5 min, 1 h, and 24 h.