Inositol signaling

Lithium Mechanism of action uncertain suppresses inositol signaling and inhibits glycogen synthase kinase-3 (GSK-3), a multifunctional protein kinase No significant antagonistic actions on autonomic nervous system receptors or specific CNS receptors no sedative effects Bipolar affective disorder-prophylactic use can prevent mood swings between mania and depression Oral absorption, renal elimination half-life 20 h. narrow therapeutic window (monitor blood levels) Toxicity Tremor, edema, hypothyroidism, renal dysfunction, dysrhythmias pregnancy category D Interactions Clearance decreased by thiazides and some NSAIDs... 

Figure 1. Schematic representation of the brain inositol signaling system. The quantities of IMPase isoenzymes and IPPase are increased by chronic lithium treatment occurring at either the gene or protein levels. Inositol in this diagram indicates the myo-inositol isomer. Calbindin -calcium binding protein DAG- diacyl glycerol Gq-GTP binding protein IMPase 1 — inositol mono phosphatase 1 IPPase- inositol polyphosphate 1-phosphatase Ins(l)P, Ins(3)P, Ins(4)P-inos-itol monophosphates Ins(l,3)P2 - inositol 1,3-bisphosphate Ins( 1,4)/ 2 - inositol 1,4-bisphos-phate Ins(3,4)/)2- inositol 3,4-bisphosphate Ins (1,4,5)P3 - inositol 1,4,5-trisphosphate Ins( 1,3,4)/ 3 - inositol 1,3,4-trisphosphate Li+-lithium PA - phosphatidic acid PI- phosphatidyl inositol PIP- phosphatidyl inositol 4-phosphate PIP2- phosphatidyl inositol 4,5-bisphosphate PIP3- phosphatidyl inositol 3,4,5 trisphosphate PLC - phospholipase-C, VPA-valproate.

There has been an increasing interest in the use of serotonin reuptake inhibitors (SSRIs) in the treatment of autism (McDougle et al., 1996). Serotonin binds to several types of receptors including the 5-HT2, and 5-HTlc receptors, which are linked to inositol signaling. A double-blind crossover study was completed at a dose of 200 mg/kg per day, and the results demonstrated no significant improvement on inositol therapy (Levine et al., 1997). 

Phosphatidyl inositol signaling PI3K, AKT, PDK, PTEN, mTOR, GSK3/1, SHIP, PLC, PKC, SHC, GRB-2, SOS, Ras, Raf, Erk, Elkl, Fos Inflammation, Rheumatoid arthritis. Cancer, Respiratory diseases... 

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

Depletion of ATP in the cells prevents maintenance of the membrane potential, inhibits the functioning of ion pumps, and attenuates cellular signal transduction (e.g., formation of second messengers such as inositol phos phates or cyclic AMP). A marked ATP depletion ultimately impairs the activ-itv of the cell and leads to ceil death. 

The NMR spectrum of d-inositol has a signal at 3.83 p.p.m. for four axial protons, and a signal at 4.10 p.p.m. for two equatorial protons. The NMR spectrum of kasugamycin contains similar signals of d-inositol. 

The power of the new spectrometer to reveal configurations of difficult cyclitols or sugars was first tested with mt/o-inositol (2), using deuterium oxide as solvent. At 60 or 100 MHz. the one equatorial and five axial protons appear to have different chemical shifts as shown by Lemieux in 1956 with a 40 MHz. instrument (14,15). However, since the five-proton axial signal could not be resolved, one could probably not have assigned the configuration 2 (which was already known from laborious chemical correlations extending over many years.)... 

Phosphatidylinositol (abbreviated Ptdlns, or PI) is a minor class of phospholipids composed of glycerol, fatty acids and inositol. Pis are found in the cytosolic side of eukaryotic cell membranes. They are substrates fora large number of enzymes which are involved in cell signalling. 

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