Phosphoinositide Signalling System

Lithium selectively interferes with the inositol lipid cycle,which is the basis for the proposal of a unifying hypothesis for lithium actions. 21122 reduces the cell concentrations of myoinositol, which would otherwise be converted to phosphatidylinositol this attenuates the response to external stimuli. -  

Neuronal and hormonal signals may often be transduced via receptor-mediated activation of phophoinositidase C (inositol lipid-directed phospholipase C), which converts phosphatidyl-inositol 4,5-bisphosphate (PIP2) to 1,2-diacyl-glycerol (1,2 DG) and D-inositol 1,4,5-triphosphate [(1,4,5)IP3] in the cell membrane. These metabolic products are second messengers 1,2 DG stimulates protein kinase C and (1,4,5)IP3 releases intracellular calcium from the endoplasmic reticulum. Subsequently, (1,4,5)IP3 is ultimately converted to myoinositol. That in turn is converted to phosphatidylinositol, which is used to replenish PIP2 stores and thus complete the cycle.  

Lithium has been shown to inhibit inositol monophosphate phosphatase uncompetitively. 2 This is an unusual mode of inhibition, which has catastrophic effects on metabolism. In a metabolic pathway at steady state, the increase in the extent of inhibition is non-linear as the products of earlier enzymes in the cycle begin to accumulate. The primary substrate at an earlier stage along the metabolic path is then rapidly depleted, and the regulation of the system as a whole soon becomes unstable and chaotic. 

Lithium also inhibits other enzymes in the interconversion and breakdown of polyphosphoinositides, though not by an uncompetitive mechanism. Either because of the uncompetitive inhibition of the monophosphatase or because of the inhibition of the other enzymes, or, indeed, by a combination of these, lithium reduces the cell concentrations of myo-inositol, which would otherwise be converted into phosphatidylinositol. The reduction in cell inositol content attenuates the brain response to external stimuli. This scheme has been suggested as 

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Sheehan M, de Belleroche J Facilitation of GABA release by cholecystokinin and caerulein in rat cerebral cortex. Neuropeptides 3 429-434, 1983 Sherman AD, Petty F Additivity of neurochemical changes in learned helplessness and imipramine. Behav Neural Biol 35 344-353, 1982 Sherman WR Lithium and the phosphoinositide signaling system, in Lithium and the Cell. Edited by Birch NJ. London, Academic Press, 1991, pp 121-157 Sherman WR, Munsell LY, Gish BG, et al Effects of systemically administered lithium on phosphoinositide metabolism in rat brain, kidney, and testis. J Neurochem 44 798-807, 1985... 

Pandey GN, Pandey SC, Isaac L, et al. Effect of electroconvulsive shock on 5HT 2 and a-adrenoceptors and phosphoinositide signalling system in rat brain [Molecular Pharmacology section], EurJ Pharmacol 1992 226 303-310. 

The Effect of AIFX on the Phosphoinositide Signaling System in the Brain... 

Phosphoinositides were shown to turn over rapidly in brain and participate in many processes of neurotransmission. The phosphoinositide signaling system is involved in the activation of muscarinic acetylcholine receptors. Early... 

Changes in Phosphoinositide Signaling System in the Brains of AD Patients... 

We observed that the incubation of platelets or red blood cells in the presence of AlFx evoked changes in the phosphoinositide signaling system and a significant decrease of platelet [Ca2+]i [68, 64]. This response was not different in platelets isolated from the blood of AD patients as compared with healthy age-matched subjects or young healthy subjects. 

We could approach the complex integrative view by the detailed study of the action of one small molecule, namely AlFx. We could also judge its role in the etiology and pathogenesis of AD on the cell level. The knowledge from studies of the phosphoinositide signaling system and Ca2+ homeostasis could help our understanding of the multifactorial nature of AD. 

Answer phosphoinositide signaling system An enzyme that catalyzes the transfer of a phosphoryl group from ATP to... 

The Affective Disorders Manic Depressive Psychoses Lithium in the Affective Disorders A. Side Effects Chemistry Isotopes of Lithium Inorganic Biochemistry Mechanisms of Action Lithium and the Phosphoinositide Signaling System Lithium and the Cell Membrane A. Sodium-Lithium Exchange Anion Exchange Leak... 

PTH acts by binding its 7-helix plasma membrane receptor to activate the adenylate cyclase/protein kinase A s naling system. In some tissues receptor binding is also coupled to the phosphoinositide signaling system to activate protein kinase C. 

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