Phosphatidylinositol 4,5 biphosphate

The latter effects were inhibited by pretreatment with antibodies to PLC-P3 but not with antibodies to other PLC-P isoezymes. They were also diminished by antibodies to the G protein P subunit but not to G protein tti and ao subunits. These results are in line with the observation that efforts to identify PTX-sensitive G protein a subunits that activate phos-phatidylinositol-phospholipase C isoenzymes have generally been unsuccessful. It is now considered that stimulation of phosphatidylinositol biphosphate hydrolysis by the PTX-sensitive G proteins, Gj and Go, involves their Py subunits (Exton 1996). Inhibition of cAMP formation was partially blocked by Gan and Gtto antibodies and additively blocked by a combination of both antibodies. SST-induced S-GTPyS-Ga complexes in plasma membranes were bound selectively by Gaii and GOo antibodies (Murthy et al. 1996). The authors concluded from these results that in smooth muscle sst3 is coupled to Gu and Go. Their a subunits mediate the inhibition of AC, while the Py subunits mediate activation of PLC-P3. Both Gai and Gao subunits are known to be moderately effective inhibitors of Ca " " - calmodulin-stimulated AC type I. Gat, in addition, also inhibits type V and VI AC (for review see Sunahara et al. 1996). 

Vinaxanthone (991) (Fig. 13.21) was isolated by Yokose and Seto in 1991 from the soil microbe, Penicillium vinaceum, and shown to be a novel phospholipase C (PLC) inhibitor, with an /C50 value in the low micromolar range (658). PLC is an enzyme that hydrolyzes phosphatidylinositol biphosphate (PIP) in the cellular membrane, and is involved in the signal transduction cascade and pathways affecting cell proliferation. Encountering difficulty in the structure elucidation process due to both the low solubility and highly substituted nature of 991, the authors used a series of NMR techniques including 2D-INADEQUATE and selective ID-INADEQUATE experiments to solve the structure. 

PHI Peptide histidine isolcucine PHM Peptide histidine methionine Pi Inorganic phosphate PI Phosphatidylinositol PI-3,4-P2 Phosphatidylinositol 3, 4-biphosphate... 

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.)...

I nositol is a simple substance present normally in the diet at about 1 g/day and is an isomer of glucose. The phosphatidylinositol (PI) cycle is an important second messenger system for several brain neurotransmitters (Figure 9-1). Receptor (R) stimulation by an activator (A) leads to breakdown of membrane phosphatidylinositol 4,5-biphosphate (PIP2) to... 

FIPhosphatidylinositol cycle. A = activator CMPPA = cytidine monophosphate phosphatidic acid DAG = diacylglycerol G = G protein Glu-6-P, glucose 6-phosphate IPj = inositol monophosphate IP2 = inositol biphosphate ... 

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. 

Micheva KD, Holz RW, Smith SJ (2001) Regulation of presynaptic phosphatidylinositol 4,5-biphosphate by neuronal activity. J Cell Biol 154 355-68 Micheva KD, Buchanan J, Holz RW, Smith SJ (2003) Retrograde regulation of synaptic vesicle endocytosis and recycling. Nat Neurosci 6 925-32... 

Inhibition of l-phosphatidylinositol-4,5-biphosphate phosphodiesterase Inhibition of translation Inhibition of DNA topoisomerase... 

Vallar, L. Muca, C. Magni, M. Albert, P. Bunzow, J.R. Meldolesi, J. Civelli, O. (1990) Differential coupling of dopaminergic D2 receptors expressed in different cell types. Stimulation of phosphatidylinositol 4,5-biphosphate hydrolysis in Ltk fibroblasts, hyperpolarization, and cytosolic-free Ca2+ concentration decrease in GH4C1 cells. J. Biol. Chem 265, 10320-10326. 

Wang, J., Gambhir, A., Hangyas-Mihalyne, G., Murray, D., Golebiewska, U., McLaughlin, S. Lateral sequestration of phosphatidylinositol 4,5-biphosphate by the basic effector domain of mystoylated alanine-rich C kinase substrate is due to nonspecific electrostatic interactions. J. Biol. Chem. 2002, 277, 34401-12. 

Rossi, M.A., Fidale, F., Garramone, A., Esterbauer, H. and Dianzani, M.U. (1990) Effect of 4-hydroxyalkenals on hepatic phosphatidylinositol-4,5-biphosphate-phospholipase C. Biochem. Pharmacol. 39 1715-1719. 

Chloroform solutions of dioleoylphosphatidylcholine (DOPC), dioleoyl-phosphatidylethanolamine (DOPE), dioleoylphosphatidylserine (DOPS), dioleoylphosphatidic acid (DOPA), and phosphatidylinositol (PI) from soybean are purchased from Avanti Polar Lipids (Alabaster, AL). Phosphatidylinositol 4-phosphate (PI4P), phosphatidylinositol 4,5-biphosphate (PIP2), and cytidine 5 -diphosphate-diacylglycerol (CDP-DAG) are obtained from Sigma (St. Louis, MO). Cholesterol is purchased from Nacalai... 

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