Evidence that inositol 1-phosphate in brain of lithium-treated rats results mainly from phosphatidylinositol metabolism

Publisher Website
Google Scholar
Abstract
In cerebral cortex of rats treated with increasing doses of LiCl, the relative concentrations of Ins(1)P, Ins(4)P and Ins(5)P (when InsP is a myo-inositol phosphate) are approx. 10:1:0.2 at all doses. In rats treated with LiCl followed by increasing doses of pilocarpine a similar relationship occurs. myo-Inositol-1-phosphatase (InsP1ase) from bovine brain hydrolyses Ins(1)P, Ins(4)P and Ins(5)P at comparable rates, and these substrates have similar Km values. The hydrolysis of Ins(4)P is inhibited by Li+ to a greater degree than is hydrolysis of Ins(1)P and Ins(5)P. D-Ins(1,4,5)P3 and D-Ins(1,4)P2 are neither substrates nor inhibitors of InsP1ase. A dialysed high-speed supernatant of rat brain showed a greater rate of hydrolysis of Ins(1)P than of D-Ins(1,4)P2 and a lower sensitivity of the bisphosphate hydrolysis to LiCl, as compared with the monophosphate. That enzyme preparation produced Ins(4)P at a greater rate than Ins(1)P when D-Ins(1,4)P2 was the substrate. The amount of D-Ins(3)P [i.e. L-Ins(1)P, possibly from D-Ins(1,3,4)P3] is only 11% of that of D-Ins(1)P on stimulation with pilocarpine in the presence of Li+. DL-Ins(1,4)P2 was hydrolysed by InsP1ase to the extent of about 50%; both Ins(4)P and Ins(1)P are products, the former being produced more rapidly than the latter; apparently L-Ins(1,4)P2 is a substrate for InsP1ase. Li+, but not Ins(2)P, inhibited the hydrolysis of L-Ins(1,4)P2. The following were neither substrates nor inhibitors of InsP1ase; Ins(1,6)P2, Ins(1,2)P2, Ins(1,2,5,6)P4, Ins(1,2,4,5,6)P5, Ins(1,3,4,5,6)P5 and phytic acid. myo-Inositol 1,2-cyclic phosphate was neither substrate nor inhibitor of InsP1ase. We conclude that the 10-fold greater tissue contents of Ins(1)P relative to Ins(4)P in both stimulated and non-stimulated rat brain in vivo are the consequence of a much larger amount of PtdIns metabolism than polyphosphoinositide metabolism under these conditions.