Lithium regulates protein tyrosine phosphatase activity in vitro and in vivo.
BACKGROUND
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.


OBJECTIVE
The present work was designed to test the effect of lithium on protein phosphatases in vitro and in vivo.


METHODS
PC12 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 PC12 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.


CONCLUSIONS
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.
Zhen
Xuechu
X
Department of Pharmacology and Physiology, CUNY Medical School, 138 Convent Ave., New York, NY 10031, USA.
Torres
Claudio
C
Friedman
Eitan
E
D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018929:Cell Culture Techniques; D002462:Cell Membrane / Q000201:enzymology; D002467:Cell Nucleus / Q000201:enzymology; D003513:Cycloheximide / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D015151:Immunoblotting; D008094:Lithium / Q000494:pharmacology*; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D004676:Myelin Basic Protein / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells; D010744:Phosphoric Monoester Hydrolases / Q000187:drug effects; D011233:Precipitin Tests; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014638:Vanadates / Q000494:pharmacology
D004676:Myelin Basic Protein; D014638:Vanadates; D020932:Nerve Growth Factor; D003513:Cycloheximide; D008094:Lithium; D010744:Phosphoric Monoester Hydrolases; C022394:phosphoserine phosphatase; D017027:Protein Tyrosine Phosphatases; D018021:Lithium Chloride