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)

Tissue transglutaminase (tTG) belongs to the family of transglutaminase enzymes that catalyze the posttranslational modification of proteins via Ca(2+)-dependent cross-linking reactions. The catalytic action of tTG results in the formation of an isopeptide bond that is of great physiological significance since it is highly resistant to proteolysis and denaturants. Although tTG-mediated cross-linking reactions have been implicated to play a role in diverse biological processes, the precise physiological function of the enzyme remains unclear. Recent data, however, suggest that the protein polymers resulting from tTG-catalyzed reactions may play a role in commitment of cells to undergo apoptosis. On the same token, tTG-mediated formation of insoluble protein aggregates may underlie the markers of numerous pathological conditions, such as the senile plaques in Alzheimer's disease and the Lewy bodies in Parkinson's disease. In addition to catalyzing Ca(2+)-dependent cross-linking reactions, tTG can also bind and hydrolyze guanosine triphosphate and adenosine triphosphate. By virtue of this ability, tTG has been identified as a novel G-protein that interacts and activates phospholipase C following stimulation of the alpha-adrenergic receptor. The ability of tTG to mediate signal transduction may contribute to its involvement in the regulation of cell cycle progression. The following review summarizes the important features of this multifunctional enzyme that have emerged as a result of recent work from different laboratories.
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PMID:Tissue transglutaminase: an enzyme with a split personality. 1048 Dec 69

Phosphoinositide-specific phospholipase C (PLC) is a key enzyme in signal transduction. A subset of muscarinic cholinergic receptors are linked to G-proteins that activate phospholipase C. Cholinergic pathways are important in learning and memory, and deficits in cholinergic transmission have been implicated in Alzheimer's disease (AD). AD is also associated with increased beta-amyloid plaques. In the present study, we have investigated the effect of the amyloid beta (A beta) synthetic peptide homologous to residue 25-35 of A beta in nonaggregated and aggregated forms on the degradation of inositol phospholipids. Synaptic plasma membranes (SPM) and the cytosolic fraction from rat brain cortex served as a source of enzymes. The studies were carried out with radioactive inositol phospholipids in the presence of endogenous and 2 mM CaCl2. The enzyme(s) activity was evaluated by determination of the product formation of [3H]inositol-1-phosphate (IP1) or [3H]inositol-1,4,5-trisphosphate (IP3). Results show that the PI-PLC activity was significantly higher in cytosol compared to SPM, and this enzyme was stimulated by 2 mM CaCl2, but not by GTPgammaS or carbachol, a cholinergic receptor agonist. Activity of the SPM-bound PIP2-PLC was similar to that in cytosol and was not activated by 2 mM CaCl2. The SPM PIP2-PLC was significantly stimulated by GTPgammaS together with the cholinergic agonist, carbachol. Fresh-water-soluble A beta 25-35 activated PI-PLC in SPM markedly by two- to threefold, but this effect was absent in the presence of 2 mM CaCl2. Moreover, A beta 25-35 had no effect on basal PIP2-PLC activity and cytosolic PI-PLC and PIP2-PLC. The aggregated form of A beta 25-35 significantly inhibited PIP2-PLC only in the presence of endogenous CaCl2. It also inhibited the carbachol and GTP(gamma)S-stimulated PIP2-PLC. Our findings show that depending on the aggregation state and Ca2+ concentration, A beta modulates phosphoinositide degradation differently and exclusively in brain synaptic plasma membranes. Our data suggested that aggregated A beta peptide may be responsible for the significant impairment of phosphoinositide signaling found in brain membranes during AD.
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PMID:Amyloid beta peptide 25-35 modulates hydrolysis of phosphoinositides by membrane phospholipase(s) C of adult brain cortex. 1052 54

Alzheimer's disease cybrid cells produced by replacing endogenous mitochondria in human neuroblastoma SH-SY5Y cells with platelet mitochondria from subjects with Alzheimer's disease have higher levels of reactive oxygen species than do cybrid cells with mitochondria from control subjects. These cells were used to test if this chronic mild increase in reactive oxygen species affects muscarinic receptor-coupled signaling activities. Basal and carbachol-stimulated phosphoinositide hydrolysis were higher, and there was less inhibition by glutathione depletion, in Alzheimer's disease than control cybrid cells. Elevated phosphoinositide hydrolysis in Alzheimer's disease cybrid cells also was evident upon direct activation of G-proteins (Gq/11) linked to phosphoinositide signaling or of phospholipase C, but immunoblot analyses revealed equivalent levels of Gq/11 and phospholipase C in both cell lines. These results indicate that there is up-regulation of phosphoinositide signaling in Alzheimer's disease cybrid cells in association with chronic mild oxidative stress, although treatment of cells with H(2)O(2) to induce greater acute oxidative stress caused decreases in carbachol-stimulated phosphoinositide hydrolysis that were similar in Alzheimer's disease and control cybrid cells. In contrast to phosphoinositide hydrolysis, carbachol-stimulated AP-1 DNA binding activity was lower in Alzheimer's disease than control cybrid cells, and this deficit was associated with deficient protein kinase C-mediated activation of AP-1. Overall, these results demonstrate that chronically elevated reactive oxygen species in Alzheimer's disease cybrid cells are associated with a more robust phosphoinositide signaling system, but lower signaling to activation of AP-1. These alterations may represent adaptations to exposure to oxidants, which precede more widespread deficits in signaling associated with more severe oxidative stress.
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PMID:Alterations in muscarinic receptor-coupled phosphoinositide hydrolysis and AP-1 activation in Alzheimer's disease cybrid cells. 1079 46

The effect of administration of aluminum to rats on the level of three phospholipase C (PLC) isozymes (beta1, gamma1, and delta1) was assessed in a variety of brain tissues. After exposure to aluminum, a statistically significant increase in malondialdehyde, an index of lipid peroxidation, was observed. In addition, there was a significant reduction in the catalytic activity of low molecular weight phosphotyrosine phosphatase, which loses its activity during oxidative stress. This suggests that oxidative stress is induced in brain tissues exposed to aluminum. The protein level of PLC-delta1, but not that of PLC-beta1 or -gamma1, was significantly increased in brains where oxidative stress had been induced. The total PLC activity in aluminum-treated rat brains was significantly higher than that in control brains. These results suggest that PLC-delta1 protein levels in brain tissues are increased by the induction of oxidative stress, giving an explanation for its up-regulation in Alzheimer's disease.
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PMID:Increase in phospholipase C-delta1 protein levels in aluminum-treated rat brains. 1081 11

The effect of sodium azide (NaN(3)) upon platelet Ca(2+) signalling has been investigated. A 60 s preincubation with 1 mM NaN(3) reduced the Ca(2+) response to 1 microM serotonin without a corresponding reduction in the responses to 52 mU/ml thrombin or 70 microM beta-amyloid(25-35) (A beta(25-35)). The effect of NaN(3) upon the response to serotonin, which was not blocked by either glutathione ethyl ester (GTEE) or dithiothreitol (DTT), was similar in platelets obtained from patients with Alzheimer's disease and from age- and gender-matched controls. After a preincubation time of 5 min was used, the Ca(2+) response to thrombin was greatly reduced by 1 mM NaN(3), but not by 50 microM 4-hydroxynonenal (HNE, 50 microM). Platelet levels of HNE and malondialdehyde were not significantly affected by up to 30 min of incubation with NaN(3) at room temperature. It is concluded that the rapid effect of NaN(3) upon the Ca(2+) response to serotonin in human platelets is not mediated by an inhibition of cytochrome c oxidase, and is due to an action proximal to phosphoinositide-specific phospholipase C.
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PMID:Rapid inhibition by sodium azide of the phosphoinositide-mediated calcium response to serotonin stimulation in human platelets: preservation in Alzheimer's disease. 1091 62

Complement defense 59 (CD59) is a cell surface glycophosphoinositol (GPI)-anchored protein that prevents complement membrane attack complex (MAC) assembly. Here, we present evidence from ELISA assays that CD59 protein levels are significantly decreased in the frontal cortex and hippocampus of Alzheimer's disease (AD) compared with nondemented elderly (ND) patients, whereas complement component 9, a final component to form MAC, is significantly increased. To further confirm the CD59 deficit, PI-specific phospholipase C (PIPLC) was used to cleave the CD59 GPI anchor at the cell surface in intact slices from AD and ND cortex. CD59 released by PIPLC cleavage was significantly reduced in AD compared with ND samples. By the use of a ribonuclease protection technique, amyloid beta-peptide was found to downregulate CD59 expression at the mRNA level, suggesting a partial explanation of CD59 deficits in the AD brain. To evaluate the pathophysiological significance of CD59 alterations in neurons, we exposed cultured NT2 cells, which normally underexpress CD59, and NT2 cells transfected to overexpress CD59 to homologous human serum. Lactic acid dehydrogenase assays revealed significant complement-induced cell lysis in CD59-underexpressing NT2 cells and significant protection from such lysis in CD59-overexpressing NT2 cells. Moreover, cells expressing normal levels of CD59 showed no evidence of MAC assembly or damage after exposure to homologous serum, whereas pretreatment of these cells with a CD59-neutralizing antibody resulted in MAC assembly at the cell surface and morphological damage. Taken together, these data suggest that CD59 deficits may play a role in the neuritic losses characteristic of AD.
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PMID:Deficiency of complement defense protein CD59 may contribute to neurodegeneration in Alzheimer's disease. 1102 7

In the present study, the effects of beta-amyloid (25-35) (Abeta (25-35)) upon calcium signalling by the human platelet has been investigated. When assays were conducted using HEPES buffers, Abeta (25-35), but not the inactive peptide Abeta (35-25), produced a robust increase in intracellular calcium that remained after removal of extracellular calcium but was abolished by the phospholipase C inhibitor U-73122. There was no significant difference between the calcium response to Abeta (25-35) in platelets from patients with Alzheimer's disease and from age-matched controls. In contrast to the robust effects on calcium mobilisation in HEPES buffers, very little calcium response to Abeta (25-35) was seen when Krebs (pH 7.8) buffer was used.
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PMID:Human platelet calcium mobilisation in response to beta-amyloid (25-35): buffer dependency and unchanged response in Alzheimer's disease. 1113 83

In the present study, the release of secreted beta-amyloid precursor protein (AbetaPPs) in response to thrombin stimulation in platelets has been investigated. Incubation of platelets with thrombin produced a concentration-dependent release of AbetaPPs with a concomitant reduction in the AbetaPP remaining in the lysates. The response to thrombin was not affected by pretreatment for 15 min with the phospholipase C inhibitor U-73122, with the protein kinase C inhibitor staurosporine, or with hydrogen peroxide (which at the concentrations used affects the phosphoinositide signalling system in human platelets). In contrast, pretreatment with wortmannin and sodium azide reduced the responses to thrombin. These data would suggest that thrombin may cause the release of AbetaPPs from human platelets via an activation of a phospholipase C-independent pathway. Thrombin-stimulated AbetaPPs release was also reduced by 4-hydroxynonenal. This finding, if it is a phenomenon also found for CNS cells, could be of relevance to the pathogenesis of Alzheimer's disease, given that an accumulation of 4-hydroxynonenal is found in this disease.
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PMID:Effects of staurosporine, U-73122, wortmannin, 4-hydroxynonenal and sodium azide upon the release of secreted beta-amyloid precursor protein from human platelets in response to thrombin stimulation. 1135 46

Based on radioligand binding studies, it has long been assumed that the neurochemical pathology of Alzheimer's disease (AD) does not involve widespread changes in post-synaptic neurotransmitter function. However, more recent studies suggest that receptor function in AD may be compromised due to disrupted post-receptor signal transduction, in particular that mediated by the G-protein regulated phosphoinositide hydrolysis and adenylate cyclase (AC) pathways. The phosphoinositide hydrolysis pathway has been shown to be altered at a number of levels in AD post-mortem brains, including impaired agonist and G-protein regulation of phospholipase C, decreased protein kinase C (PKC) levels and activity, and a reduced number of receptor sites for the second messenger, Ins(1,4,5)P3. Of these, loss of Ins(1,4,5)P3 receptors and PKC in the entorhinal cortex and hippocampus correlates with AD-related neurofibrillary changes, as staged according to Braak's protocol. Disregulation of the phosphoinositide hydrolysis pathway may therefore have consequences for the progression of AD pathology. In contrast to the extensive pattern of disruption seen with the phosphoinositide hydrolysis pathway, changes to AC signalling in AD appear more circumscribed. Disruptions include a lesion at the level of Gs-protein stimulation of AC and, at least in the hippocampus, reduced enzyme activities in response to forskolin stimulation. Of these, the latter change has been shown to precede neurofibrillary changes. Apart from a loss of calcium/calmodulin sensitive AC isoforms, other components of this signalling pathway, including G-protein levels, Gi-protein mediated inhibition and protein kinase A levels and activity, remain relatively preserved in the disorder.
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PMID:Receptor-G-protein signalling in Alzheimer's disease. 1144 33

Apolipoprotein E isoforms may have differential effects on a number of pathological processes underlying Alzheimer's disease. Recent studies suggest that the amount, rather than the type, of apolipoprotein E may also be an important determinant for Alzheimer's disease. Therefore, understanding the regulated synthesis of apolipoprotein E is important for determining its role in Alzheimer's disease. We show here that in rat primary hippocampal astrocyte cultures, dibutyryl-cAMP increased apolipoprotein E secretion with time in a dose-dependent manner (to 177% at 48 h) and that retinoic acid potentiated this effect (to 298% at 48 h). Dibutyryl-cAMP also gave a rapid, albeit transient, increase of apolipoprotein E mRNA expression (to 200% at 1 h). In contrast, the protein kinase C activator phorbol 12-myristate 13-acetate decreased both apolipoprotein E secretion (to 59% at 48 h) and mRNA expression (to 22% at 1 h). Phorbol 12-myristate 13-acetate also reversed the effects of dibutyryl-cAMP. Apolipoprotein E secretion was also modulated by receptor agonists for the adenylyl cyclase/cAMP pathway. Isoproterenol (50 nM, a beta-adrenoceptor agonist) enhanced, while clonidine (250 nM, an alpha2-adrenoceptor agonist) decreased, secreted apolipoprotein E. We also analysed the effects of agonists for the phospholipase C/protein kinase C pathway. Arterenol (1 microM, an alpha1-adrenoceptor agonist) and serotonin (2.5 microM) enhanced, whereas carbachol (10 microM, an acetylcholine muscarinic receptor agonist) decreased secreted apolipoprotein E. The effects of these non-selective receptor agonists were modest, probably due to effects on different signalling pathways. Arterenol also potentiated the isoproterenol-mediated increase. We also show that phorbol 12-myristate 13-acetate and dibutyryl-cAMP have opposite effects on nerve growth factor, as compared to apolipoprotein E, secretion, suggesting that the results obtained were unlikely to be due to a general effect on protein synthesis. We conclude that astrocyte apolipoprotein E production can be regulated by factors that affect cAMP intracellular concentration or activate protein kinase C. Alterations in these signalling pathways in Alzheimer's disease brain may have consequences for apolipoprotein E secretion in this disorder.
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PMID:Regulation of apolipoprotein E secretion in rat primary hippocampal astrocyte cultures. 1151 30


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