Phosphoinositides phosphatidylinositol phosphate

The same basic biochemical control mechanism causes contraction of the smooth muscle as well as secretion of aldosterone. The binding of angiotensin to its receptor activates a membrane phospholipase-C. It catalyses the hydrolysis of phosphoinositide phosphatidylinositol bis-phosphate to produce the two intracellular messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). 

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. 

Scheme 1. The hydrolysis and resynthesis of phosphoinositides. Hydrolysis of phosphat-idylinositol (PI), phosphatidylinositol 4-phosphate (PIP), or phosphatidylinositol 4,5-bisphosphate (PIP2) is catalyzed by PLC in the plasma membrane. The resynthesis of phosphoinositides proceeds in the endoplasmic reticulum...

Rho proteins are involved in regulation of the actin cytoskeleton and induce formation of stress fibers and focal adhesions (Paterson et al., 1990 Ridley and Hall, 1992 Tominaga et al., 1993 Laudanna et al., 1996). Most probably independently of their role in actin regulation, Rho proteins have been proposed to participate as molecular switches in the control of phosphoinositide-3-kinase (Zhang et al., 1993), phosphatidylinositol-4-phosphate-5-kinase (Chong et al.. 

A FIGURE 13-28 Synthesis of DAG and IP3 from membrane-bound phosphatidylinositol (PI). Each membrane-bound PI kinase places a phosphate (yellow circles) on a specific hydroxyl group on the inositol ring, producing the phosphoinositides... 

The key to understanding the role of phosphoinositides in the action of hormones and growth factors was the discovery that the binding of these hormones to their receptors results in the activation of phospholipase C to cleave phosphatidylinositol 4i5-bis(phosphate) (PIP2). This hormone-receptor regulated process results in the formation of 1, 2-diacylglycerol (dAG) and inositol... 

Figure 1, Phosphoinositide Pathway. Enzymes a. phosphatidyl-inositol synthetase (PI synthetase) h. phosphatidylinositol kinase (PI kinase) c. phosphatidylinositol-4-phosphate kinase (pip kinase) d. phospholipase C (R = palmitoyl or other long-chain fatty acid chain).

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]. 

When the acidic lipids of soybean cells heavily pre-labelled with [ P]Pi were resolved by 2-D TLC, no trace of radioactivity could be detected in the position occupied by a sample of authentic PI(4,5)P2 run on the same plate [34]. However [ P]-label was found at the location of a phosphatidylinositol 4-phosphate (PI(4)P) standard. This is only a preliminary to the process of proper identification. Co-chromatography of radioactivity, whether from p P]-Pi or [ H]-inositol, with a phosphoinositide standard in 1 -D TLC is not acceptable evidence of identity. It has subsequently been shown that suspension cultured cells of tomato and carrot callus also do not appear to contain detectable levels of PI(4,5)P2 [39]. 

As5mimetric total S5mthesis of isosteric and isoelectronic phosphonate analogues (31)-(33) of phosphatidylinositol 4,5-phosphate, PtdIns(4,5)P2, that cannot be hydrolysed by phospholipase-C and their biological activity, has been described. A Pd(0) coupling not previously exploited in phospholipid or phosphoinositide synthesis was employed. It was also shown that a-fluorovinylphosphonate (32) optimally restored the sensitivity of the TRPM4 channel to... 

Figure 2. The so-called canonical phosphoinositide pathway . The continuous phosphorylation/dephosphorylation reactions allow a steady-state level of Ptdins, PtdIns(4)P and PtdIns(4,5)P2 in the plasma membrane (PM). Cleavage of PtdIns(4,5)P2 by phospholipase C (PLC) generates the two well-known second messengers, inositol 1,4,5-trisphosphate (Ins(l,4,5)P3) and diacylglycerol (DAG). Besides its role as a protein kinase C (PKC) activator, DAG can be phosphorylated to phosphatidic acid (PA). The resynthesis of Ptdins from inositol and PA occurs mainly in the endoplasmic reticulum (ER). PPi, inorganic phosphate. PA-Pase, phosphatidic acid phosphatase. PA-TP, phosphatidic acid transport protein. PtdIns-TP, phosphatidylinositol transport protein. CDP-DAG, cytidine diphosphate-diacylglycerol. CMP, CDP and CTP, cytidine mono-, di- and triphosphate, respectively.

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