Functions of phosphoinositides

As discussed above, PtdIns(4)P is the major precursor of PtdIns(4,5)P2, but it can also be phosphorylated by type II PI 3-kinases to produce PtdIns(3,4)P2. 

PtdIns(4)P has been shown to bind to the cytoskeletal protein talin, suggesting that it may have a function in the cell on its own (Payrastre et al, 2001). 

Typically, the level of PtdIns(4,5)P2 is rather stable, although local increases or decreases in its concentration are likely to occur. The rapid drop observed upon phospholipase C activation does not exceed more than 40% and is immediately followed by resynthesis. 

It is noteworthy that some of the effects of Rho (Ras homolog) GTPases and ARF6 (ADP ribosylation factor 6) on the actin cytoskeleton organization might be explained by the fact that these small G-proteins can regulate the local production of PtdIns(4,5)P2 by activating the phosphoinositide kinases responsible for its formation (Toker, 2002 Yin and Janmey, 2003). 

Interestingly, Rancher et al (2000) have demonstrated that PtdIns(4,5)P2 can control the local adhesion energy between the plasma membrane and the 

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Wymann, M. P. and Pirola, L., Structure and function of phosphoinositide 3-kinases, Biochim. Biophys. Acta, 1436, 127-150, 1998. 

Katso, R, Okkenhaug, K, Ahmadi, K, White, S, Timms, J, and Waterfield, MD (2001) Cellular function of phosphoinositide 3-kinase implication for development, immunity, homeostasis and cancer. Anna Rev Cell Dev Biol, 17, 615-675. 

Brunn, G.J., Williams, J., Sabers, C., Weiderrecht, G., Lawrence, J. C., and Abraham, R. T. (1996). Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBOJ. 15, 5256-5267. 

A single enzyme, inositol monophosphatase, leads to loss of the remaining phosphate and the regeneration of free inositol. This enzyme exhibits similar affinities for all five of the equatorial inositol monophosphate hydroxyls. Inositol 2-phosphate, which is not produced in this degra-dative pathway, is a poor substrate, a property that is probably attributable to its axial configuration. The enzyme is inhibited by Li+ in an uncompetitive manner i.e. the degree of inhibition is a function of substrate concentration. The putative link between the ability of Li+ to interfere with phosphoinositide turnover and its therapeutic efficacy in the treatment of bipolar disorders is discussed in Box 20-1 and Chapter 55. It should be noted that unlike most other tissues, brain can synthesize inositol de novo by the action of inositol monophosphate synthase, which cyclizes glucose 6-phosphate to form I(3)P. The enzyme has been localized immunohistochemically to the brain vasculature. 

Katan, M. Families of phosphoinositide-specific phospholipase C structure and function. Biochim. Biophys. Acta 1436 5-17,1998. 

Rameh, L.E., and Cantley, L.C., 1999, The role of phosphoinositide 3-kinase lipid products in ceU function. J. Biol. Chem. 274 8347-83550. 

The products of the PI3-kinase reaction are different phosphoinositide derivatives phosphorylated at the 3 position, of which PtdIns(3,4,5)P3 has the greatest regulatory importance. PtIns(3,4,5)P3, like cAMP, has the function of a messenger substance that activates effector molecules in the sequence for further signal conduction. In contrast to cAMP, Ptdlns(3,4,5)P3 is localized in the cell membrane and performs its function in close association with processes at the cell membrane. 

Further studies have revealed that pumiliotoxin B interacts with voltage-dependent sodium channels to elicit an increased influx of sodium ions (101,102) and, in brain and heart preparations, a stimulation of phosphoino-sitide breakdown (101,103-106). The phosphoinositide breakdown can, via inositol trisphosphate, cause release of calcium from internal storage sites. The cardiotonic activity of pumiliotoxin B and various congeners and synthetic analogs correlates well with the stimulation of phosphoinositide breakdown (104,105). A number of studies on stimulation of sodium uptake by pumiliotoxin B and inhibition by local anesthetics and other agents have appeared (106-108). The effects of pumiliotoxin B on neuromuscular preparations have been reinterpreted as due primarily to effects on sodium channels, although additional direct effects on calcium mobilization remain possible (109). It has recently been proposed that pumiliotoxin B enhances the rate of activation of sodium channels (110). One characteristic effect of pumiliotoxin B is to elicit repetitive firing in neurons, apparently because of effects on sodium channel function (109-111). 

Stephens, L., McGregor, A., and Hawkins, P., 2000, Phosphoinositide 3-kinases Regulation by cell-surface receptors and function of 3-phosphorylated lipids. In S. Cockcroft (ed.), Frontiers in Molecular Biology, Vol. 27, Biology of phosphoinositides. Oxford University Press, New York, pp. 32-108. 

Cracking the Green Paradigm Functional Coding of Phosphoinositide Signals in Plant Stress Responses... 

AND FUNCTIONAL SPECIFICITY OF PHOSPHOINOSITIDES DURING CELLULAR HOMEOSTASIS AND OSMOTIC STRESS... 

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