DICTYOSTELIUM-DISCOIDEUM CONTAINS 3 INOSITOL MONOPHOSPHATASE ACTIVITIES WITH DIFFERENT SUBSTRATE SPECIFICITIES AND SENSITIVITIES TO LITHIUM

The small ion lithium, a very effective agent in the treatment of mani c depressive patients, inhibits the mammalian enzyme inositol monophos phatase, which is proposed as the biological target for the effects of lithium. In this study we investigated Dictyostelium discoideum inosi tol monophosphatase activity. Partial purification of the proteins in the soluble cell fraction using anion-exchange chromatography revealed the presence of at least three enzyme activities capable of degrading inositol monophosphate isomers. The first activity was similar to the monophosphatase found in mammalian cells, as it degraded Ins(4)P, Ins (1)P and to a lesser extent Ins(3)P, was dependent on MgCl2 and inhibi ted by LiCl in a non-competitive manner. The second enzyme activity wa s specific for Ins(4)P; the enzyme activity was not dependent on MgCl2 and not inhibited by LiCl. The third monophosphatase activity degrade d especially Ins(3)P, but also Ins(4)P and Ins(1)P; increasing concent rations of MgCl2 inhibited this enzyme activity, whereas LiCl had no e ffect. In vivo, LiCl induces a reduction of inositol levels by about 2 0%. In [H-3]inositol-labelled cells LiCl causes a 6-fold increase in t he radioactivity of [H-3]Ins(1)P, a doubling of [H-3]Ins(4)P and a sli ght decrease in the radioactivity in [H-3]Ins(3)P. These data indicate that the biological effects of lithium in Dictyostelium are not due t o depletion of the inositol pool by inhibition of inositol monophospha tase activity.