Phosphatidylinositols PIP

Figure 4 Schematic representation of the Ca2+-transporting systems affecting cellular calcium homeostasis during hormonal stimulation, oq = oq-adrenergic receptor VP = vasopressin receptor PLC = phospholipase C PI = phosphatidylinositol PIP = phospha-tidylinositol-4-phosphate PIP2 = phosphatidylinositol-4,5-biphosphate IP3 = inositol-1,4,5-triphosphate DG = diacylglycerol PKC = protein kinase C. (Modified from Refs. 125 and 285.)...

IP3 = 1,4,5-inositol triphosphate PI = phosphatidylinositol PIP = phosphatidylinositol phosphate PIP2 = phosphatidylinositol 4,5-biphosphate PKC = protein kinase C PLC = phosphohpase C R = receptor T = transporter. 

Fig. 1. Stimulus-induced turnover of phosphatidylinositol 4,5-bisphosphate (PIPo) and the role of turnover products in signal transduction. PI, phosphatidylinositol PIP, phosphatidylinositol 4-phosphate PIPo, phosphatidylinositol 4,5 bisphosphate IP, inositol trisphosphate IP, inositol tetrakisphosphate IPo inositol bisphosphate IP, inositol monophosphate ER, endoplasmic reticulum DG, diacylglycerol MG, monoglyceride AA, arachidonic acid PA, phosphatidic acid. [Adapted from 38]...

D, salina cells grown in our standard 1.71 M NaCl medium contained phosphatidylinositol 4,5-bisphosphate (PIP ) and phosphatidylinositol 4-phosphate (PIP) as well as phosphatidylinositol. PIP and PI 2 highly localized within the... 

Figure 6.6. Structure and formation of phosphatidylinositol (Ptdlns), phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5-bisphosphate (PIP2). See text for details.

Neutrophil membranes contain inositol lipids, which comprise about 5-6% of the total membrane lipids. About 80% of these inositol lipids possess stearic acid (Cl8 0) at Cl and arachidonic acid (C20 4) at C2 positions. Phosphatidylinositol accounts for most of these lipids (90%), with smaller amounts of PIP (6%) and PIP 2 (4%), which are synthesised sequentially by the action of 4- and 5-specific kinases, respectively (see Fig. 6.6). Neutrophil membranes also possess a phosphatidylinositol-specific phospholipase C which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into Ins 1,4,5 P3 and DAG (Fig. 6.7). Both PLC-/3(/ 2) and PLC-y (72) families appear to be present in neutrophils. The coupling of receptor occupancy to PLC activation in neutrophils can be through a heterotrimeric G-protein, the mobile subunit of which has been termed G p. Evidence for this G-protein link comes from the following facts ... 

Sequence of Events From Receptor to Protein Kinase Cyclic AMP (cAMP) and Phosphatidylinositol Bisphosphate (PIP )... 

Figure 11.21 Outline of synthesis of phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine and phosphatidylcholine. Note in the synthesis of phosphatidylinositol, the free base, inositol, is used directly. Inositol is produced in the phosphatase reactions that hydrolyse and inactivate the messenger molecule, inositol trisphosphate (IP3). This pathway recycles inositol, so that it is unlikely to be limiting for the formation of phosphatidylinositol bisphosphate (PIP )- This is important since inhibition of recycling is used to treat bipolar disease (mania) (Chapter 12, Figure 12.9). Full details of the pathway are presented in Appendix 11.5. Inositol, along with choline, is classified as a possible vitamin (Table 15.3).

Figure 12.19 Phosphatidylinositol bisphosphate cycle and treatment of bipolar disease. The metal ion lithium inhibits inositol monophosphate phosphatases and, therefore, inhibits the flux from IP3 to inositol, so that the concentration of the latter decreases. This can restrict formation of phosphatidylinositol the bisphosphate (PIP ) so that the amount in the membrane decreases and the phospholipase no longer catalyses a zero order reaction. The extent of the decrease in the IP3 concentration will depend on how far the process is removed from zero order. This may explain the well-known variability in the response of patients to lithium which is probably dependent on the patient taking the precise dose of the drug (Chapter 14).

When attention is directed toward the phospholipase.C found in mammalian tissue, a rather unique and different substrate profile is evident. It appears that the most favored substrate status must be assigned to the inositol- containing phosphoglycerides, namely, phosphatidylinositol (PI), phosphatidylinositol phosphate (PIP), and phosphatidylinositol-4,5-bisphosphate (PIP2). There is some evidence that the plasma membrane of certain mammalian cells contains a phospholipase C with high specificity for the bisphosphate, PIP2. The latter enzymatic interaction would be closely associated with the signal transduction pathway in mammalian cells. 

Abbreviations [Ca2+]j, intracellular Ca2+ concentration as measured by a Ca2 indicator such as ae-quorin [Ca2+]c, Ca2+ concentration in the bulk cytosol (hypothetical value) [Ca2 f]sm, Ca2 concentration in submembrane domain just beneath the plasma membrane (a hypothetical value) PI, phospha-tidylinositol PIP2, phosphatidylinositol 4,5-bisphosphate PIP, phosphatidylinositol 4-phosphate Insl,4,5,P3, inositol 1,4,5,-trisphosphate Ins 1,3,4,P, inositol 1,3,4-trisphosphate Insl,3,4,5P4, inositol 1,3,4,5-tetrakisphosphate Insl,4P2, inositol 1,4-bisphosphate CaM, calmodulin C-kinase, protein kinase C [cAMP]c, cAMP concentration in the bulk cytosol [cAMP]sm, cAMP concentration in submembrane domain just beneath the plasma membrane. 

Fig. 2. A schematic representation of some of the mechanisms by which Car fluxes across the plasma membrane are regulated. In the plasma membrane (the striped area) there are both influx (=>) and energy-dependent ( ) efflux pathways. Two mechanisms by which Ca2+ influx can be increased are via the actions of the intracellular messengers inositol 1,3,4,5-tetrakisphosphate, and cAMP generated via activation of specific classes of surface receptors (R, and R2) linked to specific N proteins which activate either phosphatidylinositol 4,5-bisphosphate (PIP,) hydrolysis or adenylate cyclase (AC). Additionally, influx can be increased either by a direct receptor-coupled event or by a membrane depolarization (not shown). A rise in the Ca2+ concentration in the domain just beneath the plasma membrane, [Ca2+Isin, can lead to an activation of the Ca2+ pump either via a direct calmodulin (CaM)-dependent mechanism, or indirectly via the activation of protein kinase C (CK). Additionally, in some cells, an increase in cGMP concentration also increases Ca2+ efflux (not shown), and in still others cAMP may stimulate Ca2 efflux.

Phosphatidylinositols and their phosphorylated deri tives are substrates for several Ptdins kinases. For example, Ptdins is converted by Ptdins 3-kinase to PtdIns-3-P, by Ptdins 4-kinase to PtdIns-4-P, and by Ptdins 5-kinase to PtdIns-5-P. Moreover, PtdIns-3-P is converted by phosphatidylinositol phosphate 4-kinase, (PIP 4 kinase), to PtdIns-3,4-P2, and PtdIns-4-P is converted by PIP 3-kinase to PtdIns-3,4-P2 and to PtdIns-4,5-P2 by PIP 5-kinase. Finally, PtdIns-4,5-P2 is hydrolysed by phospholipase C to diacylglycerol (DAG) and IP3, and the Ptdins bisphosphates (PtdIns-3,4-P2 and... 

PIP2 is formed in the cell membrane by the successive phosphorylation of the membrane phospholipid phosphatidylinositol (PI) to phosphatidylinositol 4-monophosphate (PIP) and then to PIP2. PIP2 is readily recycled by specific phosphomonoesterases to PIP and eventually back to PI. This cycle continues at rest until stimulation of surface receptors occurs. Receptor... 

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