Previous studies showed that
lithium, beginning at therapeutic plasma concentrations in the treatment of
manic depression, increased the accumulation of second-messenger
inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] in cerebral cortex slices of guinea pig and rhesus monkey [Lee, Dixon, Reichman, Moummi, Los and Hokin (1992) Biochem. J. 282, 377-385; Dixon, Lee, Los and Hokin (1992) J. Neurochem. 59, 2332-2335; Dixon, Los and Hokin (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 8358-8362]. These studies have now been extended to a peripheral tissue, mouse pancreatic minilobules. In the presence of
carbachol, concentrations of
lithium from 1 to 20 mM sharply and progressively increased the accumulation of Ins(1,4,5)P3 and
inositol 1,3,4,5-tetrakisphosphate, followed by a decrease. Assay of these
inositol polyphosphates by either the prelabelling technique or mass assay gave similar results.
Atropine quenching of cholinergically stimulated pancreatic minilobules led to a rapid disappearance of Ins(1,4,5)P3. This disappearance was impeded by
lithium. This suggested that the
lithium-induced elevation in Ins(1,4,5)P3 was due to inhibition of the 5-phosphatase and, on the basis of the markedly elevated concentrations of
inositol 1,3,4-trisphosphate [Ins(1,3,4)P3] and
inositol 1,4-bisphosphate in the presence of
lithium, probably by feedback inhibition by these latter two compounds. An additional mechanism, i.e. a stimulatory effect of
lithium on
phospholipase C, cannot, however, be ruled out. The other reaction product of
phospholipase C,
inositol cyclic 1:2,4,5-trisphosphate, also increased in the presence of
lithium. This may also be due to inhibition of the 5-phosphatase, which is the exclusive mechanism for removal of this compound. The effects of
lithium on the accumulation of other
inositol phosphates paralleled that of Ins(1,4,5)P3, with the exception of
inositol 3,4-bisphosphate, which decreased. This was presumably due to the inhibition of Ins(1,3,4)P3 1-phosphatase by
lithium. Unlike mouse cerebral cortex slices [Lee, Dixon, Reichman, Moummi, Los and Hokin (1992) Biochem. J. 282, 377-385],
inositol supplementation was not required to demonstrate
lithium-stimulated Ins(1,4,5)P3 accumulation in mouse pancreatic minilobules. This indicates that
inositol depletion sufficient to impair
lithium-stimulated Ins(1,4,5)P3 accumulation does not occur in mouse pancreatic minilobules, even though an elevation of
cytidine diphosphodiacylglycerol occurred, indicating some
inositol depletion due to
lithium. Elevation of Ins(1,4,5)P3 by
lithium may be a general phenomenon in the central nervous system and peripheral tissues under non-rate-limiting concentrations of
inositol.