Inositol trisphosphate breakdown

In Uver, adrenaline binds to the a-receptor, and the hormone-receptor complex activates a membrane-bound phospholipase enzyme which hydrolyses the phospholipid phosphatidylinositol 4,5-bisphosphate. This produces two messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG) (Figure 12.5). The increase in IP3 stimulates release of Ca ions from the endoplasmic reticulum into the cytosol, the effect of which is glycogen breakdown and release into the blood (see Figure 12.5 and Chapter 6). 

Activation of phospholipase C leads to cleavage of the membrane phospholipid phosphatidylinositol 4,5-bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG). 1P3 promotes release of Ca2+ from storage organelles, whereby contraction of smooth muscle cells, breakdown of glycogen, or exocytosis may be initiated. DAG stimulates protein kinase C, which phosphorylates certain serine- or threonine-containing enzymes. 

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). 

Little is known of the intracellular events involved in the augmentation of cyclic AMP accumulation elicited by H, -receptors in mammalian brain slices. However, it seems certain that another second messenger is involved, since the effect is not observed in membrane preparations [81, 205]. Calcium appears to be important for the response, since removal of external calcium reduces H,-receptor-mediated cyclic AMP accumulation in guinea-pig cerebral cortical slices [206]. Inositol phospholipid breakdown or its products (inositol trisphosphate and diacylglycerol) may also be involved, since H,-receptor stimulation is accompanied by an accumulation of inositol phosphates in slices of guinea-pig cerebral cortex [60, 207, 208]. Inositol trisphosphate may then... 

Many oncogenes such as ras, src, sis, fms, and fes enhance cellular PI turnover. Phosphatidyl breakdown by phospholipase C generates two second messengers, diacyIglycerol and inositol trisphosphate. The formed directly activates protein kinase C, and the latter binds to the receptor on endoplasmic reticulum to mobilize calcium ions. Therefore, we screened culture filtrates of microorganisms for inhibitors of PI turnover and thus isolated psi-tectorigenin (Fig. 11, ref. 23). ... 

Hormonal factors and other stimuli by activating phospholipase C-(3 or -y isoforms stimulate the breakdown of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate and diacylglycerol, a reaction called PI response. 

A further intriguing aspect of the biological chemistry of cyclic inositol phosphates lies in the fact that they are not only detected as products of hydrolysis of PIPj catalysed by phospholipase C, but they may also be intermediates in this enzyme-catalysed reaction. The water-soluble products of the breakdown of PIPj catalysed by phospholipase C were hydrolysed in 0-labelled water in the presence of acid (Wilson et al., 1985a,b). The resulting trisphosphates after work-up were analysed by mass spectrometry-gas chromatography. Since only reactive cyclic phosphates are hydrolysed (with label incorporation) in dilute acid, Majerus and coworkers were able to use this technique to quantify the initial cyclic phosphate product of the phospholipase C reaction. Similar experiments were performed with phosphatidyl inositol 4-monophosphate (PIP) and phosphatidyl inositol (PI) as substrates and the results confirmed by hplc ananlysis. 

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