Inositol phosphate metabolic cycle

An additional action of Li" is interruption of the phosphatidylinositide cycle through an inhibitory action on inositol phosphate metabolism. By this mechanism, depletion of membrane inositol and the phosphoinosi-tide-derived second-messenger products diacylglycerol and inositol triphosphate ultimately reduces signaling through receptor systems dependent on the formation of these products. It is presently unclear to what extent inhibition of inositol phosphate metabolism contributes to the therapeutic properties of Li+ in bipolar patients. 

The inositol phosphates are linked into a metabolic cycle (Fig. 6.5) in which they can be degraded and regenerated. Via these pathways, the cell has the ability to replenish stores of inositol phosphate derivatives, according to demand. Ptdins may be regenerated from diacylglycerol via the intermediate levels of phosphatidic acid and CDP-glycerol. 

Fig. 4. Metabolism of inositol lipids and inositol phosphates in stimulated cells. In the lipid cycle. Ptdlns is converted through Ptdlns 4-P to Ptd 4,5-P, which is hydrolysed upon receptor stimulation to yield diacylglycerol (DG) and Ins(1.4,5)P,. DG is phosphorylated via diacylglycerol kinase to give phospha-tidic acid (PA). PA is activated by CTP to form CDP-diacylglycerol which can combine with free inositol (Ins) to re-form Ptdlns. The other product of the Ptdlns 4,5-P, hydrolysis, Ins(l,4,5)P, may be de-phosphorylated to various InsP2 and InsP isomers which ultimately provide free inositol (Ins) for resynthesis of Ptdlns. Ins(l,4,5)Pj may be phosphorylated in steps to give an array of InsP4, InsP, or InsP6 isomers.

Biswas, B.B., Biswas, S., Chakrabarti, S., and De, B.P., 1978a, A novel metabolic cycle involving myo-inositol phosphates during formation and germination of seeds. In Wells, W.W. and Eisenberg, E, Jr. (eds.), Cyclitols and Phosphoinositides. Academic Press, New York, pp. 57-68. 

A further effect of lithium on receptor-activated cells is accumulation of diacylglycerol, which may increase or prolong the activation of protein kinase C (107). It should be noted that diacylglycerol and D-inositol l,4,5-tris(phosphate) are separate branches of two parallel signaling systems that initially are coherent. Metabolic interference by lithium to desynchronize these systems may itself be a signaling system. This is analogous with beat phenomena seen in the desynchronization of biological cycles by rapid movement between time zones. 

Lithium selectively interferes with the inositol lipid cycle [42,43] and this is the basis for a proposal of a unifying hypothesis for lithium actions [44,45]. Administration of lithium to rats (10 mmol/kg) resulted in a reduction in brain myoinositol and an increase in the reaction substrate inositol-1 -phosphate [46]. The magnesium-dependent enzyme inositol monophosphate phosphatase was inhibited in rat mammary gland by lithium [47]. Lithium has been shown to inhibit inositol monophosphate phosphatase in bovine brain ( (j = 0.8 mM) by substituting noncompetitively for magnesium ions [48]. Lithium may also affect other enzymes involved in phosphoinositide metabolism [43,49]. Lithium reduces the cell concentrations of myoinositol, which would otherwise be converted to phosphatidylinositol, and this attenuates the response to external stimuli [43,50]. 

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