Phosphoinositide signaling system

The transduction of many hormonal and neuronal signals occurs through receptor-mediated activation of phosphoinositidase C (phospholipase C). This enzyme hydrolyzes phosphatidylinositol 4,5-bis-(phosphate) (PIP2) into 1,2-diacylglycerol and n-inositol 1,4,5-tris-(phosphate) in the plasma membrane. Both products are second messengers that, respectively, stimulate protein kinase C and release calcium from intracellular stores located in the endoplasmic reticulum (100). D-Inositol l,4,5-tris(phosphate) is converted via intermediary compounds to myoinositol. In return this is converted to phosphatidylinositol, which is used to replenish PIP2. 

Lithium selectively interferes with the inositol lipid cycle (100) and this is the basis for a proposal of a unifying hypothesis for lithium actions (96). Administration of lithium to rats (10 mmol/kg) resulted in a reduction in brain myoinositol and an increase in the reaction substrate inositol-l-phosphate (101). The magnesium-dependent enzyme inositol monophosphate phosphatase, which catalyzes the conversion of inositol monophosphates to inositol, was totally inhibited in rat mammary gland by high concentrations of lithium (250 mM) and partially inhibited by lower concentrations (2 mAf) (102). At clinically relevant concentrations lithium has been shown to inhibit inositol monophosphate phosphatase in bovine brain (K, = 0.8 mM) by substi- 

Lithium reduces the cell concentrations of myoinositol, which would otherwise be converted to phosphatidylinositol. This reduction in cell inositol lipid content ultimately attenuates the response to external stimuli (107). This has been suggested as the mechanism of action of lithium in the affective disorders, because plasma sources of inositol cannot cross the blood-brain barrier and brain cells must therefore rely on endogenous supplies (96). 

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. 

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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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