Lithium regulates protein tyrosine phosphatase activity in vitro and in vivo

Rationale: Lithium has been shown to regulate multiple intracellular signaling pathways by affecting various protein kinases. However, the counterpart of protein kinases, i.e., protein phosphatases may play an important role in lithium-regulated cellular signaling and functions. Objectives: The present work was designed to test the effect of lithium on protein phosphatases in vitro and in vivo. Methods: PC 12 cells were used as an in vitro model to characterize the effect of lithium on protein phosphatase activity. Rats treated with a lithium-containing diet were used to examine the in vivo effect of the drug on brain protein phosphatase activity. Results: Lithium stimulated protein tyrosine phosphatase (PTPase) activity in a dose- and time-dependent manner in PC12 cells. A maximal stimulation of 87% was observed after 6 h of incubation with 3 mM LiCl. In contrast, protein serine phosphatase (PSPase) activity was not changed by lithium. The stimulatory effect on PTPase was not due to a direct action of the ion on the enzymes, but its selectivity was noted since treatment of cells with other monovalent cations exhibited no effect on PTPase activity. Lithium appeared to target specific PTPase(s) as it stimulated membrane-associated PTPase activity without affecting cytosolic or nuclear enzymatic activities. Moreover, the stimulation of PTPase activity in PC 12 cells by lithium is independent of de novo protein synthesis. In the rat, 3 weeks of lithium treatment significantly elevated PTPase activity in hippocampus, striatum and cortex. Conclusion: The present findings provide the first evidence that lithium treatment selectively increases membrane-associated PTPase activity and suggest that this action may contribute to the pharmacotherapeutic actions of lithium.