Reduced inositol polyphosphate accumulation and inositol supply induced by lithium in stimulated cerebral cortex slices

Abstract

The ability of lithium to interfere with phosphoinositide metabolism in rat cerebral cortex slices has been examined by monitoring the accumulation of CMP-phosphatidate (CMP-PtdOH) and the reduction in Ins(1,4,5)P3 and Ins(1,3,4,5)P4 levels. A small accumulation of [14C]CMP-PtdOH was seen in slices prelabelled with [14C]cytidine and stimulated with carbachol (1 mM) or Li+ (1 mM). However, simultaneous addition of both agents for 30 min produced a 22-fold accumulation, with Li+ producing a half-maximal effect at a concentration of 0.61 +/- 0.19 mM. Kinetic studies revealed that the effects of carbachol and Li+ on CMP-PtdOH accumulation occurred with no initial lag apparent under these conditions and that preincubation with myo-inositol (10 or 30 mM) dramatically attenuated CMP-PtdOH accumulation. myo-Inositol could also attenuate the rate of accumulation of CMP-PtdOH when added 20 min after carbachol and Li+; these effects were not observed when equimolar concentrations of scyllo-inositol were added. Use of specific radioreceptor assays allowed the mass accumulations of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 to be monitored. Following a lag of 5-10 min, Li+ resulted in a marked reduction in the accumulation of both inositol polyphosphates resulting from muscarinic-cholinergic stimulation. Preincubation of cerebral cortex slices with myo- (but not scyllo-) inositol delayed, but did not prevent, the reduction in the accumulation of Ins(1,4,5)P3 or Ins(1,3,4,5)P4. The results suggest that cerebral cortex, at least in vitro, is very sensitive to myo-inositol depletion under conditions of muscarinic receptor stimulation. The relationship of such depletion to the generation of inositol polyphosphate second messengers is discussed.

The Phospholipase C-IP3 Pathway is Involved in Muscarinic Antinociception

“…To investigate the IP 3 -mediated pathway, LiCl, an uncompetitive inhibitor of inositol monophosphatase, which regenerates inositol from inositol monophosphate, was used. The LiCl-induced inhibition depletes inositol and prevents the formation of IP 3 (Kennedy et al, 1990;Phiel and Klein, 2001). Animals pretreated with LiCl showed an impaired antinociceptive response to the administration of physostigmine and oxotremorine.…”

Phospholipid Synthesis Participates in the Regulation of Diacylglycerol Required for Membrane Trafficking at the Golgi Complex

“…Because the growth medium of CHO cells contains a 100 M concentration of each substrate, the medium was replaced by a saline-buffered solution. When choline and inositol were not present, lithium was added to inhibit inositol monophosphatases and thus to reduce the amount of endogenous inositol available (35,36). The total amount of DAG was higher in lipid extracts from NRK and CHO-K1 cells incubated for 1 h in the absence of the substrates than in their presence (Fig.…”

Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks

“…24,25 While it was posited that lithium produces its therapeutic effects via a consequent reduction in relative concentrations of myo-inositol and PIP 2 concentrations, data-driven support for this hypothesis has been highly dependent upon the cell and animal models under investigation. [26][27][28][29][30][31] Much of this inconsistency may be related to the relatively small size of the signal- Figure 1 Lithium-responsive signal transduction pathways focused on PI/PKC and GSK-3 signaling. Lithium directly inhibits the enzyme inositol monophosphate phosphatase (IMPase; K i E0.8 mM).…”