Phosphoinositide Metabolism

The relatively small pool of the precursor for Ins(l,4,5)P3, the phospholipid PtdIns(4,5)P2, is synthesized from the larger reservoir of phosphatidylinositol (Ptdlns) and, therefore, the supply of PtdIns(4,5)P2 

The profound effects of Li+ upon phosphoinositide metabolism and cell signaling have been the subject of several recent reviews [54,81,85,86]. These effects are dependent upon receptor stimulation of the phosphoinositide cycle by a range of stimuli, including norepinephrine, serotonin, and carbachol the basal turnover of this cycle is largely unaffected by Li+ [82,87,88]. 

Li+ was first found to interfere with inositol lipid metabolism when significantly decreased levels of myo-inositol were observed in the cerebral cortex of Li+-treated rats [89]. Subsequent work revealed a corresponding increase in the levels of Ins( 1 )P [90] and this behavior was shown to be the result of a Li+-induced inhibition of IMPase, the enzyme which dephosphorylates the monophosphates Ins(l)P, Ins(3)P, and Ins(4)P to produce free inositol [91]. These results stimulated much research in this field involving a wide variety of cell types, tissues, and animals where the Li+ inhibition of IMPase was found to be ubiquitous. However, it was found that, in vivo, this Li+-induced effect is predominantly limited to the brain, being observed in different regions of the brain to different extents, with similar results for both acute and chronic treatment with Li+. It is probable that those cells that are able to accumulate inositol, or which are exposed to and can rapidly import an extracellular supply of inositol, may be relatively insensitive to the effects of Li+. 

The Li+-induced inhibition of IMPase also results in increases in the levels of the other monophosphates, Ins(3)P, and Ins(4)P, although the increase is less than for Ins(l)P in the brain. Increases in the levels of the bisphosphates are also observed and these increases are believed to be related to the Li+-induced inhibition of another enzyme in this cycle, inositol polyphosphate 1-phosphatase [92], which dephosphorylates both Ins(l,3,4)P3 and Ins(l,4)P2, producing Ins(3,4)P2 and Ins(4)P, re- 

The decreased level of free inositol leads to a reduction in the rate of Ptdlns resynthesis and to the subsequent accumulation of cytidine mo-nophosphorylphosphatidate (CMP-PA), the cosubstrate for the resynthesis, and of the other lipid metabolites, phosphatidic acid (PA) and DAG 

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Transduction mechanism Inhibition of adenylyl cyclase stimulation of tyrosine phosphatase activity stimulation of MAP kinase activity activation of ERK inhibition of Ca2+ channel activation stimulation of Na+/H+ exchanger stimulation of AM PA/kainate glutamate channels Inhibition of forskol in-stimulated adenylyl cyclase activation of phos-phoinositide metabolism stimulation of tyrosine phosphatase activity inhibition of Ca2+ channel activation activation of K+ channel inhibition of AM PA/ kainate glutamate channels inhibition of MAP kinase activity inhibition of ERK stimulation of SHP-1 and SHP-2 Inhibition of adenylyl cyclase stimulation of phosphoinositide metabolism stimulation of tyrosine phosphatase activation of K+ channel inhibi-tion/stimulation of MAP kinase activity induction of p53 and Bax Inhibition of adenylyl cyclase stimulation of MAP kinase stimulation of p38 activation of tyrosine phosphatase stimulation of K+ channels and phospholipase A2 Inhibition of adenylyl cyclase activation/ inhibition of phosphoinositide metabolism inhibition of Ca2+ influx activation of K+ channels inhibition of MAP kinase stimulation of tyrosine phosphatase... 

Other enzymes present in myelin include those involved in phosphoinositide metabolism phosphatidylinositol kinase, diphosphoinositide kinase, the corresponding phosphatases and diglyceride kinases. These are of interest because of the high concentration of polyphosphoinositides of myelin and the rapid turnover of their phosphate groups. This area of research has expanded towards characterization of signal transduction system(s), with evidence of G proteins and phospholipases C and D in myelin. 

The observed Li+-induced stimulation of corticotropin (ACTH) secretion from cells in culture, requiring extracellular Ca2+, involves a corresponding and apparently associated increase in the concentration of Ins(l)P, indicating some interaction with phosphoinositide metabolism [176], Pretreatment with Li+ desensitizes the cells, reducing this Li+-induced stimulation of ACTH secretion. Li+ initially raises plasma cortisol levels in manic-depressives however the levels are subsequently reduced with chronic Li+ treatment in both patients and controls [177]. This effect is probably secondary to the stimulation and subsequent desensitization of ACTH secretion by Li+, as observed in cultured cells. 

Costa LG, KaylorG, Murphy SD. 1986. Carbachol-and norepinephrine-stimulated phosphoinositide metabolism in rat brains Effect of chronic cholinesterase inhibition. J Pharmacol Exp Ther 239 32-37. 

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... 

Sherman WR, Gish BG, Honchar MP, et al Effects of lithium on phosphoinositide metabolism in vivo. Federation Proceedings 45 2639-2646, 1986 Shingai R, Sutherland ML, Barnard EA Effects of subunit types of the cloned GABAa receptor on the response to a neurosteroid. Eur J Pharmacol 206 77-80, 1991 Shipley JE, Kupfer DJ, Griffin SJ, et al Comparison of effects of desipramine and amitriptyline on EEG sleep of depressed patients. Psychopharmacology 85 14-22, 1985... 

Bleasdale, J. E., Eichberg, J., and Hauser, H. (19B6. itol and Phosphoinositides Metabolism and Regulation Human Press Inc., Clifton, NJ. 

Mundy WR, Freudenrich T, Shafer TJ, et al. 1995. In vitro aluminum inhibition of brain phosphoinositide metabolism Comparison of neonatal and adult rats. Neurotoxicology 16 35-44. 

Winkler JD, Sarau HM, Foley JJ et al. (1988) Leukotriene B4-induced homologous desensitization of calcium mobilization and phosphoinositide metabolism in U-937 cells. J Pharmacol Exp Ther 246 204-210... 

Undie AS, Weinstock J, Sarau HM, Friedman E (1994) Evidence for a distinct Dl-like dopamine receptor that couples to activation of phosphoinositide metabolism in brain. J Neurochem 62 2045-2048. 

Phosphoinositide Metabolism Towards an Understanding of Subcellular Signaling... 

Boss, W.F., 1989, Phosphoinositide metabolism Its relation to signal transduction in plants, in Boss, W.F., Morre, D.J. (ed) Second Messengers in Plant Growth and Development. New York, Alan R. Liss, pp 29-56. 

Perera, I.Y., Love, J., Heilmann, I., Thompson, W.F., and Boss, W.F., 2002, Up-regulation of phosphoinositide metabolism in tobacco cells constitutively expressing the human type I inositol polyphosphate 5-phosphatase. Plant Physiol. 129 1795-1806. 

Sherman, W.R., Leavitt, A.L., Honchar, M.P., Hallcher, L.M., Packman, P.M., and Phillips, B.E., 1981b, Evidence that lithium alters phosphoinositide metabolism Chronic administration elevates primarily D-myo-inositol-1-phosphate in cerebral cortex of the rat. J. Neurochem. 36 1947-1951. 

Yildiz, A., Demopulos, C.M., Moore, C.M., Renshaw, P.F., and Sachs, G.S., 2001, Effect of lithium on phosphoinositide metabolism in human brain A proton decoupled r3l)P magnetic resonance spectroscopy study. Biol. Psychiatry 50 3-7. 

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