Phosphatidyl inositol bisphosphate

Fig. 5.24 Classification of the phospholipases and the reaction of phospholipase C. a) Cleavage specificity of phospholipases Al, A2, C and D. b) Cleavage of inositol-containing phosphohpids by phospholipase C. In a reaction of particnlar importance for signal transduction, phosphohpase C (PL-C) catalyzes the cleavage of phosphatidyl inositol-4,5-bisphosphate (PtdIns(4,5)P2) into the messenger substances diacylglycerol and inositol 1,4,5-triphosphate (Ins(l,4,5)P3).

Phosphatidyl inositol (Ptdins) is first phosphorylated by specific kinases at the 4 and 5 positions of the inositol residue, leading to formation of phosphatidyl inositol-4,5-bisphosphate (PtdIns(4,5)P2). 

The large amount of work in this area reported by Russian workers and covered in our previous review [1] has also been reviewed by the Russian workers [284], These glycolipids have recently acquired a vastly increased biological interest since the discovery that various agonists at the cell surface stimulate a phospholipase which releases D-wiyo-inositol 1,4,5-trisphosphate from the membrane-bound phosphatidyl-inositol-4,5-bisphosphate. The released inositol trisphosphate acts as a second messenger by mobilising intra-cellular calcium ions [285-290]. 

A number of other factors activate phospholipase C which causes the hydrolysis of phosphatidyl inositol(4,5)bisphosphate to DAG and IP3. Following release the IP3 is rapidly broken down via IP2 and IP3 to inositol in a Li+ sensitive reaction and this is the reason why lithium can desensitise receptors. The inositol then reacts with activated DAG and is rephosphorylated to regenerate phosphatidyl inositol(4,5)bisphosphate (Berridge and Irvine, 1984 Wakelam, 1989). 

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.

Phospholipids, such as phosphatidyl inositol-4,5-bisphosphate and IP3, have been shown to associate with PH domains, (ref. 49 of Chapter 3). The aminoacids in the PH domain which are responsible for this interaction are Y (tyrosine), W (tryptophan), K (lysine), R (arginine), and S (serine). In many PH-domains there is a group of lysines and arginines. (This ribbon model was reproduced with permission of the authors and Nature from data in ref. 48 of Chapter 3, available in protein data banks.)... 

Likewise, phosphatidyl inositol is formed by the transfer of a diacylglycerol phosphate unit from CDP-diacylglycerol to inositol. Subsequent phosphorylations catalyzed by specific kinases lead to the synthesis of phosphatidyl inositol 4,5-bisphosphate, an important molecule in signal transduction. Recall that hormonal and sensory stimuli activate phospholipase C, an enzyme that hydrolyzes this phospholipid to form two intracellular messengers—diacylglycerol and inositol 1,4,5-trisphosphate (Section 15.2). 

Phospholipase C cleaves the membrane lipid phosphatidyl inositol 4,5-bisphosphate into two second messengers diacylglycerol, which remains in the membrane, and inositol 1.4,5-trisphosphate, which diffuses away from the membrane. 

Figure 14,12 Phosphoinositide cascade. The cleavage of phosphatidyl inositol 4,5-bisphosphate (PIP ) into diacyiglycerol (DAG) and inositol 1,4,5-trisphosphate (IP5) results in the release of calcium ions (due to the opening of the IP3 receptor ion channels) and the activation of protein kinase C (due to the binding of protein kinase C to free DAG in the membrane). Calcium ions bind to protein kinase C and help facilitate its activation.

The answer is c. (Murray, pp 238-249. Scriver, pp 2367-2424. Sack, pp 159-175. Wilson, pp 287-317.) A variety of agonists activate the plasma membrane-bound enzyme phospholipase C, which hydrolyzes the phosphodiester bond of phosphatidyl inositol 4,5-bisphosphate and consequently releases diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). Phospholipase C is also known as phosphoinositidase and as polyphosphoinositide phosphodiesterase. Both DAG and IP3 are second messengers. DAG activates protein kinase C, which is important in controlling cell division and cell proliferation. IP3 opens calcium channels and allows the rapid release of the calcium stores in endoplasmic reticulum (in smooth muscle, sarcoplasmic reticulum). The elevated levels of calcium ion stimulate smooth-muscle contraction, exocytosis, and glycogen breakdown. 

In various rat blood vessels, there is a direct correlation between expression of the ttiA AR subtype and the importance of extracellular Ca " in muscle contraction [40]. In rabbit aorta, similar results were found for the o,A-AR-extracellular Ca dependence [41]. In the same study, a parallel correlation was observed for Oib-ARs coupling to PLC and mobilization of intracellular Ca stores. These observations led to the hypotheses that oia-ARs couple to Cz influx while uig-ARs couple to phosphatidyl inositol (4,5) bisphosphate (PI) hydrolysis and release of intracellular Ca stores to trigger blood vessel contraction. 

The plasma membrane contains the phospholipid phosphatidyl inositol (Ptdlns), in which the phosphate group is esterified with a cyclic alcohol, myo-D-inositol (Fig. 6.4). Starting from Ptdlns, a series of enzymatic transformations lead to the generation of a diverse number of second messengers. Ptdlns is first phosphorylated by specific kinases at the 4 and 5 positions of the inositol residue, leading to the formation of phosphatidyl inositol-4,5-bisphosphate [PtdIns(4,5)P2]. 

IP3 is formed as a product in the hydrolysis of a special phospholipid present in the cell membrane phosphatidyl-inositol-4,5-bisphosphate. This reaction, then, is the initial receptor-stimulated event. The newly formed 1,4,5-IP3 is assumed to diffuse into the cytoplasm, and eventually reach intracellular... 

Arguably the most rapidly expanding area of research in biological phosphate chemistry over the past two or three years has been in the area of inositol phosphates. Agonist-induced stimulation of inositol-phospholipid metabolism results in hydrolysis of phosphatidyl inositol 4,5-bisphosphate... 

Neuronal and hormonal signals may often be transduced via receptor-mediated activation of phophoinositidase C (inositol lipid-directed phospholipase C), which converts phosphatidyl-inositol 4,5-bisphosphate (PIP2) to 1,2-diacyl-glycerol (1,2 DG) and D-inositol 1,4,5-triphosphate [(1,4,5)IP3] in the cell membrane. These metabolic products are second messengers 1,2 DG stimulates protein kinase C and (1,4,5)IP3 releases intracellular calcium from the endoplasmic reticulum. Subsequently, (1,4,5)IP3 is ultimately converted to myoinositol. That in turn is converted to phosphatidylinositol, which is used to replenish PIP2 stores and thus complete the cycle. ... 

Draw the structure of phosphatidyl inositol 4,5-bisphosphate (PIPj). 

Figure 1. Model of signal transduction in the snake VN system. Ligand binding to a G-protein (G)-coupled receptor (R) activates a phosphatidyl inositol-specific phospholipase C (PLC) which, in turn, hydrolyzes phosphatidyl inositol 4,5-bisphosphate (PIP2) producing diacylglyserol (DAG) and 1,4,5-inositol trisphosphate (IP3). IP3 acts directly on IP3 receptors on the smooth endoplasmic reticulum to release calcium (Ca ) from intracellular stores and on an IP3- sensitive Ca channel in the cell membrane allowing calcium influx from the extracellular space. The elevated levels of intracellular Ca results in activation of the ryanodine receptor (RyR) on the membrane of the endoplasmic reticulum, resulting in additional Ca release from intracellular stores, a phenomenon known as calcium-induced calcium release (CICR). Intracellular Ca levels return to prestimulation levels by efflux of Ca and influx of sodium (NA ) through a NAV Ca exchanger.

The total synthesis of a novel hybrid lipid Pea-PIPi (51), possessing a phosphatidyl ethanolamine (PE) headgroup at the 1-position and a phosphatidyl inositol 4,5-bisphosphate PtdIns(4,5)1 2] headgroup at the 4-position has been elaborated. Reporter groups (biotin, fluorophores, spin label) were... 

Abbreviations DAG, diacylglycerol LPA, lyso phosphatidic acid LPIP, lyso phosphatidyl inositol 4-phosphate PA, phosphatidic acid PC, phosphatidyl choline PE, phosphatidyl ethanolamine PG, phosphatidyl glycerol PI, phosphatidyl inositol PIP, phosphatidyl inositol 4-phosphate PIP2 phosphatidyl inositol 4,5-bisphosphate ... 

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