Inositol phospholipids trisphosphate

Figure 14-3. Signaling through protein kinase C (PKC). Activated phospholipase C cleaves the inositol phospholipid PIP2 to form both soluble (IP3) and membrane-associated (DAG) second messengers. DAG recruits PKC to the membrane, where binding of calcium ions to PKC fully activates it. To accomplish this, IP3 promotes a transient increase of intracellular concentration by binding to a receptor on the endoplasmic reticulum, which opens a channel allowing release of stored calcium ions. PIP2, phosphatidylinositol 4,5-bisphosphate DAG, diacylglycerol PLC, phospholipase C IP3, inositol trisphosphate.

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... 

Figure 2.13. Histamine H,-receptor-mediated inositol phospholipid hydrolysis. Stimulation of H,-receptors leads to activation of a phospholipase C. probably via a guanine-nucleotide regulatory protein (N). which catalyses the hydrolysis of phosphatidylinositol 4.5 -bisphosphate (PIP2) to give inositol trisphosphate (IP3) and 1,2-diacylglycerol (DG). IP3 is then broken down by phosphatases to eventually yield free myo-inositol. Lithium ions can inhibit the conversion of inositol 1-phosphate (IP,) to myo-inositol. Free inositol then interacts with CDP-diacylglycerol,formed by a reaction between phosphatidic acid (PA) and CTP, to yield phosphatidylinositol (PI). Phosphorylation of PI by kinases completes the lipid cycle by reforming PIP2. Modified from [147,148].

It is now generally accepted that both of the products of phosphatidylinositol 4,5-bisphosphate hydrolysis can function as intracellular second messengers. 1,2-Diacylglycerol can affect a variety of intracellular processes by activation of protein kinase C [ 148, 229, 230]. Inositol 1,4,5-trisphosphate, on the other hand, has been shown to release calcium ions from non-mitochondrial stores in a number of peripheral tissues and may thus be the link between the receptor and the intracellular calcium store in many pharmacological responses [231-233]. Furthermore, it remains a possibility that inositol phospholipid hydrolysis may also have a r61e in calcium gating [221,234]. If inositol phospholipid metabolism is closely coupled to receptor-mediated calcium mobilization, then this response may be a more general consequence of H,-receptor stimulation than other H,-responses. 

The triethylsilyl ether 147 thus formed regiospecifically from the diol 150 [Rl=(BnO)2 (0), R2=Bn], which was optically resolved by a chiral column chromatography, was transformed to Ins(2,4,5)P3 and Ins(l,4,5)P3 (Schema 3-23). At this stage, temporary protection of OH-1 with the silyl group is not necessary, i.e. 150 can be directly phosphorylated by the phosphite-phosphonium approach as described in the section on phosphorylation (Scheme 2-6). H The diol 150 was used furthermore as a versatile synthetic intermediate for the synthesis of myo-inositol 1,2-cyclic-4,5-trisphosphate 152 (Scheme 3-23), 8 2-acyl analogues of Ins(1,4,5)P3, and inositol phospholipid. 

It has been indicated that the phosphodiesteratic cleavage of the Inositol phospholipids (phospholipase C activity) precedes and might trigger the activation of phospholipase A2 in stimulated platelets.1l >20,21 It seems that some of the products formed during the phosphodiesteratic cleavage of the inosltides could be related to Ca2+ mobilization. One of these products, myoinositol 1,4,5-trisphosphate. 

FIGURE 2. Post-receptor events initiated by H2- and H,-receptor activation by histamine (HIS). Adenylate cyclase (AC) stimulation occurs directly via H2-receptor activation or possibly indirectly via a calmodulin-calmodulin binding protein complex. Membrane inositol phospholipid (IPL) hydrolysis to inositol trisphosphate (IP3) is triggered by phospholipase C (PC) activation following H,-receptor stimulation. 

The other activity associated with transmembrane receptors is phospholipase C. Phosphatidyl inositol is a membrane phospholipid that after phosphorylation on the head group is found in the membrane as a phos-photidylinostitol bis phosphate. Phospholipase C cleaves this into a membrane associated diacylglycerol (the lipid part) and inositol trisphosphate (IP3, the soluble part). Both play a later role in elevating the level of the second messenger, Ca2+. 

Alternative second-messenger pathways may be at work in olfactory transduction. The role of cAMP in olfactory transduction is well established. Are there alternative pathways, such as those involving phospholipids and Ca2+ Several groups have reported that certain odorants can elicit an increase in the phosphoinositde second messenger inositol 1,4,5,-trisphosphate (IP3) (Ch. 20). However, there is no clear evidence that IP3 directly mediates an electrical response in OSNs, nor is there a clear rationale for two parallel excitatory odor transduction cascades. However, more recent data support the idea that phos-phoinositides or enzymes related to their metabolism may play a modulatory role, shaping the OSN output by... 

The phosphorylated phospholipid, phosphatidylinositol bisphosphate, is present in cell membranes. On hydrolysis by a phospholipase, it produces two products, inositol trisphosphate and diacylglycerol (Figure 11.25), as follows ... 

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). 

A selection of other tumor suppressor genes is summarized in Table 14.2. Interestingly, an enzyme of phosphatidyl-inositol metabolism has been also identified as a tumor suppressor. The PTEN tumor suppressor gene codes for a phospholipid phosphatase which specifically cleaves a phosphate from the second messenger phosphatidyl-inosi-tol-3,4,5-trisphosphate (PtdInsPj, see 6.6.2). and thus inactivates the messenger (review Maehama and Dixon, 1999). ... 

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