Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence shows that the mature Thy-1 surface glycoprotein lacks the C-terminal amino acids 113 to 143 predicted from the cDNA sequence and is anchored in the plasma membrane by a complex, phosphatidylinositol-containing glycolipid attached to the alpha-carboxyl group of amino acid 112. Here we studied the biosynthesis of Thy-1 in two previously described and two newly isolated Thy-1-deficient mutant cell lines. Somatic cell hybridization indicated that their mutations affected some processing step rather than the Thy-1 structural gene. The Thy-1 made by mutants of classes C, F, and H bound detergent but, in contrast to wild-type Thy-1, their detergent-binding moieties could not be removed by phospholipase C. In addition, tryptophan, which only occurs in position 124, was incorporated into Thy-1 of these mutants but not of wild-type cells. Last, the Thy-1 of wild-type but not mutant cells could be radiolabeled with [3H]palmitic acid. Together, these findings strongly suggest that mutants of classes C, F, and H accumulate a biosynthetic intermediate of Thy-1 which retains at least part of the hydrophobic C-terminal peptide. The Thy-1 of these mutants remained endoglycosidase H sensitive, suggesting that it accumulated in the rough endoplasmic reticulum or the Cis-Golgi. A different Thy-1 intermediate was found in a class B mutant cell line: the Thy-1 of this mutant was 2 kilodaltons smaller than the Thy-1 of other cell lines, did not bind detergent, and was rapidly secreted via a normal secretory pathway.
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PMID:No glycolipid anchors are added to Thy-1 glycoprotein in Thy-1-negative mutant thymoma cells of four different complementation classes. 289 21

Pathogenic staphylococci secrete a number of exotoxins, including alpha-toxin. alpha-Toxin induces lysis of erythrocytes and liposomes when its 3S protein monomers associate with the lipid bilayer and form a hexomeric transmembrane channel 3 nm in diameter. We have used alpha-toxin to render rat hepatocytes 93-100% permeable to trypan blue with a lactate dehydrogenase leakage less than or equal to 22%. Treatment conditions included incubation for 5-10 min at 37 degrees C and pH 7.0 with an alpha-toxin concentration of 4-35 human hemolytic U/ml and a cell concentration of 13-21 mg dry wt/ml. Scanning electron microscopy revealed signs of swelling in the treated hepatocytes, but there were no large lesions or gross damage to the cell surface. Transmission electron microscopy indicated that the nucleus, mitochondria, and cytoplasm were similar in control and treated cells and both had large regions of well-defined lamellar rough endoplasmic reticulum. Comparisons of the mannose-6-phosphatase and glucose-6-phosphatase activities demonstrated that 5-10 U/ml alpha-toxin rendered cells freely permeable to glucose-6-phosphate, while substantially preserving the selective permeability of the membranes of the endoplasmic reticulum and the functionality of the glucose-6-phosphatase system. Thus, alpha-toxin appears to have significant potential as a means to induce selective permeability to small ions. It should make possible the study of a variety of cellular functions in situ.
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PMID:Permeabilization of rat hepatocytes with Staphylococcus aureus alpha-toxin. 298 73

Enzyme, electrolyte and fluid secretion from exocrine glands is stimulated by neurotransmitters and peptide hormones. Whereas for some of these secretagogues calcium is an important intracellular messenger, for others it is cyclic AMP. Regulation of steady state free Ca2+ concentration at rest and at stimulation have been studied in isolated permeabilized acinar cells from pancreas, parotid and lacrimal glands by measuring the free Ca2+ concentration of the surrounding incubation medium with a Ca2+-specific macroelectrode. Ca2+ transport mechanisms have been further characterized in subcellular membrane fractions by measuring 45Ca2+ uptake into membrane vesicles from rough endoplasmic reticulum (RER) and plasma membranes (PM). The data show that the intracellular messenger for secretagogue-induced Ca2+ release from RER is inositol-1,4,5-trisphosphate (IP3) which is produced during stimulation by phospholipase C mediated hydrolysis of phosphatidylinositol-bisphosphate. At rest both Ca2+ uptake into RER and Ca2+ extrusion from the cell is promoted by (Ca2+ + Mg2+)-ATPases with different characteristics in both types of membranes and by a coupled Na+/Ca2+ countertransport in the PM which keep cytosolic free Ca2+ concentration at a low level of approximately 2 - 4 X 10(-7) mol/l. During stimulation the Ca2+ permeability of endoplasmic reticulum membrane increases via IP3 and that of the PM by a yet unknown "receptor-operated" mechanism. These events lead to increase in cytosolic free Ca2+ concentration that is a trigger for enzyme, electrolyte and fluid secretion.
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PMID:Stimulus-secretion coupling in exocrine glands: the role of inositol-1,4,5-trisphosphate, calcium and cAMP. 299 Aug 22

Many hormones, neurotransmitters, and secretagogues act by increasing the intracellular free Ca2+ concentration in target cells. The initial event following binding of agonists to specific receptors in the plasma membrane involves a receptor-mediated activation of a guanosine nucleotide-binding protein (G protein), which induces a Ca2+-independent activation of phospholipase C. This novel, presently uncharacterized G protein is inactivated by pertussis toxin-catalyzed adenosine 5'-diphosphate ribosylation in some but not all cell types. Phospholipase C catalyzes the breakdown of inositol lipids, notably phosphatidylinositol 4,5-bisphosphate, with the production of inositol phosphates and 1,2-diacylglycerol. Inositol 1,4,5-trisphosphate (IP3) is responsible for a rapid mobilization of intracellular Ca2+ by activating Ca2+ efflux from a subpopulation of the endoplasmic reticulum. The properties of this process are consistent with its being a ligand-activated ion channel with electrogenic Ca2+ efflux being charge-compensated by K+ influx. Sustained hormonal responses require extracellular Ca2+ and a prolonged elevation of the cytosolic free Ca2+. This is brought about by hormone-mediated changes of Ca2+ flux across the plasma membrane involving both an inhibition of Ca2+ efflux and an activation of Ca2+ influx. This review summarizes recent findings concerning the role of G proteins in receptor coupling to phospholipase C; the regulation of enzymes of phosphoinositide metabolism; the evidence for IP3 being a Ca2+-mobilizing second messenger and its mechanism of action; the formation of new inositol phosphates and their possible significance; the relation of intracellular Ca2+ mobilization and plasma membrane Ca2+ fluxes to the kinetics of the hormone-induced cytosolic free Ca2+ transient; and the possible roles of protein kinase C in influencing the hormone-mediated functional response.
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PMID:Role of inositol lipid breakdown in the generation of intracellular signals. State of the art lecture. 301 67

Evidence from a variety of laboratories indicates that crosslinking of B cell mIg induces a rapid increase in intracellular free calcium (Ca++i). This mobilized Ca++ appears to act in concert with diacylglycerol (DAG; also released upon mIg cross-linking) to optimally activate Ca++/phospholipid-dependent protein kinase C, which plays a pivotal role in B cell activation. Here we report analysis of the source of this mobilized calcium and the mechanism responsible for its release into the cytosol. We observed the cross-linking of mIg induces the release of inositol 1,4,5-trisphosphate (InsP3), presumably as a result of action of phospholipase C on plasma membrane phosphatidylinositol 4,5-bisphosphate (PtdInsP2). The release of InsP3 and the elevation of Ca++i are coincidental, suggesting that they may be causally related. Finally, we demonstrate that submicromolar doses of InsP3 induce release of Ca++ from permeabilized cells that had preaccumulated 45Ca++ in the endoplasmic reticulum. On the basis of these findings we suggest that mIg cross-linking leads to mobilization of Ca++, in part by causing hydrolysis of PtdInsP2, yielding InsP3, which in turn causes release of calcium from the endoplasmic reticulum.
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PMID:Anti-Ig induces release of inositol 1,4,5-trisphosphate, which mediates mobilization of intracellular Ca++ stores in B lymphocytes. 301 2

A wide variety of receptors appear to be coupled to a phospholipase C (EC 3.1.4.3) that hydrolyzes inositol lipids. This reaction is believed to provide a link between receptor activation and cellular Ca2+ mobilization. The mechanisms by which this occurs are believed to involve inositol 1,4,5-trisphosphate (1,4,5-IP3), which signals release of Ca2+ from the endoplasmic reticulum. In rat parotid acinar cells made permeable with saponin, 1,4,5-IP3 induced rapid release of sequestered Ca2+. In intact parotid cells, the concentration-response relationship for methacholine-induced IP3 formation was similar to the relationship for muscarinic receptor occupancy by methacholine. About 10-fold lower concentrations of methacholine were sufficient to increase cytosolic [Ca2+] and to activate secretion, indicating an excess IP3 forming capacity for the muscarinic receptor. The mechanisms for the coupling of receptors to IP3 formation were studied in pancreatic acinar cells made permeable electrically. In this preparation, nonhydrolyzable derivatives of GTP potentiated agonist-induced IP3 production, which suggests the involvement of a guanine nucleotide-dependent regulatory protein. The effects of agonists and guanine nucleotides were not altered by pretreating the acinar cells with cholera or pertussis toxins, which indicated that the regulatory protein linking receptors to IP3 formation is distinct from the ones involved in the regulation of adenylate cyclase.
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PMID:Formation and biological action of inositol 1,4,5-trisphosphate. 301 83

A variety of surface membrane receptors can activate a phospholipase C, which degrades phosphatidylinositol 4,5-bisphosphate liberating a calcium mobilizing second messenger, inositol 1,4,5-trisphosphate [(1,4,5)IP3]. The coupling of surface receptors to the phospholipase C involves one or more guanine nucleotide-dependent regulatory proteins that are similar but not identical to those that regulate adenylate cyclase. (1,4,5)IP3 has been shown to release Ca2+ from a portion of the endoplasmic reticulum and is believed responsible for the initial phase of Ca2+ mobilization ascribed to internal Ca2+ release. (1,4,5)IP3 acts by binding to a specific receptor that either is a component of, or regulates, a Ca2+ ion channel. The release of Ca2+ from the (1,4,5)IP3-sensitive component of the endoplasmic reticulum may secondarily activate the second phase of Ca2+ mobilization, which involves Ca2+ entry. (1,4,5)IP3 is metabolized by two pathways. One involves the action of a 5-phosphatase that degrades (1,4,5)IP3 to inositol 1,4-bisphosphate, whereas the other involves a 3-kinase that phosphorylates (1,4,5)IP3 to produce inositol 1,3,4,5-tetrakisphosphate. The significance of this dual metabolism is not known, but it may be important in rapidly extinguishing the Ca2+-releasing activity (1,4,5)IP3.
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PMID:Formation and actions of calcium-mobilizing messenger, inositol 1,4,5-trisphosphate. 303 Jan 26

A number of plasma membrane glycoproteins of mammalian and protozoan origin are released from cells by phosphatidylinositol-specific phospholipase C. Some of these proteins have been shown to be attached to the lipid bilayer via a covalently linked, structurally complex glycophospholipid. Here we establish the existence of similarly linked glycoproteins in the yeast Saccharomyces cerevisiae. The most abundant of these is a tightly membrane-bound glycoprotein of 125 kd. The detergent-binding moiety of this protein can be removed by phosphatidylinositol-specific phospholipase C of bacterial origin or from Trypanosoma brucei. Metabolic labeling indicates that the protein contains covalently attached fatty acid and inositol. It also contains the cross-reacting determinant (CRD), an antigen found previously on the glycophospholipid anchor of protozoan and mammalian origin. Treatment of the protein with endoglycosidases F and H results in a 95-kd species. In the secretion mutant sec18, grown at 37 degrees C, the vesicular transport of glycoproteins is reversibly blocked between the rough endoplasmic reticulum and the Golgi apparatus. We find that sec18 cells, when grown at 37 degrees C, do add phospholipid anchors to newly synthesized glycoproteins. This indicates that these anchors are added in the rough endoplasmic reticulum.
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PMID:A major 125-kd membrane glycoprotein of Saccharomyces cerevisiae is attached to the lipid bilayer through an inositol-containing phospholipid. 304 36

One or more phospholipases of the C and A2 types exist in rodent islets and may play a pivotal role in the cell signaling cascade culminating in exocytotic insulin release. Phospholipase C generates myo-inositol-1,4,5-trisphosphate, which mobilizes a "pool" of calcium in the endoplasmic reticulum and which may also secondarily facilitate calcium (Ca++) influx from the extracellular space to replenish that pool. Diacylglycerol is also generated by phospholipase C action and activates protein kinase C; it may thereby potentiate the cellular response to elevations in cytosolic free Ca++ concentration. Arachidonic acid may be released during the degradation of diacylglycerol and may also contribute to islet activation. Phospholipase C is activated by glucose, cholinergic agonists, and probably by Ca++ fluxes. Phospholipase A2 action generates arachidonic acid and lysophospholipids. Certain lysophospholipids mobilize cellular Ca++, at least in part from superficial, plasmalemmal stores. Native (unoxygenated) arachidonic acid also has the capability of mobilizing cellular Ca++ from membrane-bound stores; it may, in addition, activate protein kinase C, as suggested by recent indirect studies. The further metabolism of arachidonic acid via lipoxygenase and cyclo-oxygenase appears to provide positive and negative modulation, respectively, of stimulated insulin secretion. Many pieces of the puzzle remain, however, to be supplied. For example, it has not yet been unequivocally demonstrated that phospholipase A2 is activated by physiologic stimuli in intact islets. Furthermore, the absence of truly specific pharmacologic stimulators or inhibitors of these processes currently precludes precise delineation of the respective physiologic roles of each potential mediator in stimulus-secretion coupling. When such roles are elucidated, it can be asked whether the defects in insulin secretion in diabetes mellitus may be due in part to abnormalities in the turnover of beta-cell membrane phospholipids and the generation of intracellular lipid-derived signals.
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PMID:Membrane phospholipid turnover as an intermediary step in insulin secretion. Putative roles of phospholipases in cell signaling. 305 98

Many hormones are capable of increasing [Ca2+]i in many different tissues by mobilizing Ca2+ from internal stores, primarily the endoplasmic reticulum, and by promoting Ca2+ influx across the plasma membrane. Recent studies suggest that both processes involve G-proteins. In one case, a G-protein activates a PI 4,5-P2 specific phospholipase C, resulting in the formation of Ins 1,4,5-P3, which then releases Ca2+ from the endoplasmic reticulum. Ca2+ influx can be stimulated by low concentrations of agonist, which do not promote internal Ca2+ mobilization. This process appears to be stimulated directly by a G-protein.
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PMID:Hormonal modulation of cytosolic free calcium. 305 7


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