Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

beta 1-Integrins are major mediators of interactions between cells and extracellular matrix (ECM). Adhesion of rat glomerular epithelial cells (GEC) to collagen stimulated phospholipase C. As a result, 1,2-diacylglycerol (DAG) was increased, and inositol phospholipids were decreased in collagen-adherent cells, as compared with GEC adherent to plastic substrata. Adhesion to collagen also stimulated production of free arachidonic acid (the precursor for eicosanoids) due to metabolism of DAG through the DAG lipase pathway and due to phospholipase A2-induced hydrolysis of phospholipids. Phospholipase A2 appeared to be stimulated as a result of protein kinase C (PKC) activation, probably secondary to increased DAG. The collagen-induced increases in DAG and free arachidonic acid, as well as the decrease in inositol phospholipids, were partially inhibited by lowering extracellular Ca2+ concentration to 200 nM or less and by anti-beta 1-integrin antibody Fab. In contrast, anti-beta 1-integrin immunoglobulin G (IgG) enhanced collagen-mediated increases in DAG and arachidonic acid. Proliferation of GEC adherent to collagen was reduced in the presence of anti-beta 1-integrin IgG. The antiproliferative effect of anti-beta 1-IgG appeared to be mediated through PKC, since it was absent in PKC-depleted GEC. Immunoprecipitation with integrin subunit-specific antibodies demonstrated alpha 2 beta 1- and alpha 3 beta 1-integrins in GEC. Thus, in GEC, ECM induces activation of phospholipases C and A2, which is mediated, at least in part, by beta 1-integrins. Products of integrin-mediated phospholipase activation may modulate GEC proliferation.
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PMID:Extracellular matrix-stimulated phospholipase activation is mediated by beta 1-integrin. 844 65

Repetitive mechanical stimulation of cultured avian skeletal muscle increases the synthesis of prostaglandins (PG) E2 and F2 alpha which regulate protein turnover rates and muscle cell growth. These stretch-induced PG increases are reduced in low extracellular calcium medium and by specific phospholipase inhibitors. Mechanical stimulation increases the breakdown rate of 3H-arachidonic acid labelled phospholipids, releasing free 3H-arachidonic acid, the rate-limiting precursor of PG synthesis. Mechanical stimulation also increases 3H-arachidonic acid labelled diacylglycerol formation and intracellular levels of inositol phosphates from myo-[2-3H]inositol labelled phospholipids. Phospholipase A2 (PLA2), phosphatidylinositol-specific phospholipase C (PLC), and phospholipase D (PLD) are all activated by stretch. The stretch-induced increases in PG production, 3H-arachidonic acid labelled phospholipid breakdown, and 3H-arachidonic acid labelled diacylglycerol formation occur independently of cellular electrical activity (tetrodotoxin insensitive) whereas the formation of inositol phosphates from myo-[2-3H]inositol labelled phospholipids is dependent on cellular electrical activity. These results indicate that mechanical stimulation increases the lipid-related second messengers arachidonic acid, diacylglycerol, and PG through activation of specific phospholipases such as PLA2 and PLD, but not by activation of phosphatidylinositol-specific PLC.
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PMID:Mechanical stimulation of skeletal muscle generates lipid-related second messengers by phospholipase activation. 846 70

Epidermal enzymes play an important role in the process of differentiation of keratinocytes. The present preliminary in vitro study was undertaken to observe if topical enzyme treatment influenced permeation of compounds across the skin. Due to the noted function and importance of phosphatidylcholine metabolism during maturation of the barrier lipids, the effects of topical application of the phosphatidylcholine dependent phospholipase C enzyme (not present in epidermis) on skin penetration of three model drugs, viz. benzoic acid, mannitol and testosterone, were studied. Similar studies were also carried out using epidermal enzymes like triacylglycerol hydrolase, acid phosphatase, and phospholipase A2 (present in epidermis). Pretreatment of skin with phospholipase C significantly enhanced permeation of benzoic acid, mannitol, and testosterone relative to untreated skin. Triacylglycerol hydrolase (neutral) increased the penetration of mannitol 3-fold and had no effect on benzoic acid penetration. Topical application of acid phosphatase did not alter the permeation of any of these compounds. Phospholipase A2 significantly enhanced permeation of benzoic acid and mannitol while it did not have any effect on the penetration of testosterone. These results for the first time demonstrate that enzymes may remarkably affect and/or regulate the permeation of topically applied compounds.
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PMID:Epidermal enzymes as penetration enhancers in transdermal drug delivery? 869 22

It is an established fact that animals recovering from prior acute renal failure (ARF) are resistant to subsequent renal failure challenge with the same toxic agents, although the detailed mechanisms responsible for this phenomenon remain unclear. In this study, the mechanism underlying acquired resistance to gentanmicin (GM) was investigated from the viewpoint of kidney tissue enzymology. Sprague-Dawley rats (N = 40) were administered GM subcutaneously at the dose of 80mg/day consecutively for 40 days. Blood urea nitrogen (BUN) reached the maximum mean concentration of 36 mg/dl on day 14. Thereafter, it decreased to a level within the normal range on day 21. The change in fractional excretion of sodium (FENa) showed a curve virtually identical to the change in BUN. In renal tissue, the elevation of malondialdehyde (MDA) levels was transient during continued administration of GM. The shingomyelin (SPH)/phosphatidylcholine (PC) ratio significantly decreased on day 4, but there was no marked change thereafter. The levels of total phospholipids (PLs), phosphatidylcholine (PC), and phosphatidylethanolamine (PE) increased, whereas SPH decreased mostly on day 4. The levels of phosphatidylinositol (PI) showed a continued fall during the 40 days of the experiment. On day 40, these changes in composition recovered. Phospholipase A2 (PLA2) activities decreased gradually, whereas a distinct increase in phospholipase C (PLC) activity was maintained after day 21. Furthermore, glutathione (GSH) levels also showed two distinct cycles of decrease and increase. PLs levels correlated well with PLC activities. It was concluded that accelerated lipid peroxidation occurs early in the course of GM administration and enhances changes in the phospholipid composition, which has an influence on membrane fluidity. Thus, acquired resistance to ARF induced by GM may be due to the supply of GSH and the maintenance of alteration in phospholipid composition, which are induced by PLC activities.
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PMID:[An experimental study on the pathogenetic role of acquired resistance to acute renal failure--Enzymochemical investigation]. 871 8

We have previously shown that 24,25-(OH)2D3 plays a major role in resting zone (RC) chondrocyte differentiation and that this vitamin D metabolite regulates protein kinase C (PKC). The aim of the present study was to identify the signal transduction pathway used by 24,25-(OH)2D3 to stimulate PKC activation. Confluent, fourth passage RC cells from rat costochondral cartilage were used to evaluate the mechanism of PKC activation. Treatment of RC cultures with 24,25-(OH)2D3 for 90 min produced a dose-dependent increase in diacylglycerol (DAG). Addition of R59022, a diacylglycerol kinase inhibitor, significantly increased PKC activity in cultures treated with 24,25-(OH)2D3. Addition of dioctanoylglycerol (DOG) to plasma membranes isolated from RC increased PKC activity 447-fold. Addition of pertussis toxin or cholera toxin to control cultures elevated basal PKC activity. When added together with 10(-9) M 24,25-(OH)2D3, there was an additive effect on PKC activity but in cultures treated with 10(-8) M 24,25-(OH)2D3, only the hormone-dependent stimulation of PKC was observed. The phospholipase C inhibitor, U73-122, had no effect on PKC activity, indicating that the DAG produced in response to 24,25-(OH)2D3 is not derived from phosphatidylinositol. Addition of the tyrosine kinase inhibitor, genistein, also had no effect on 24,25-(OH)2D3-stimulated PKC, further supporting the hypothesis that phospholipase C is not involved in the mechanism and that phospholipase D is responsible for the increase in DAG production. Phospholipase A2 inhibitors, quinacrine and AACOCF3, and the cyclooxygenase inhibitor indomethacin increased PKC activity in the RC cultures. Exogenous PGE2, one of the downstream products of phospholipase A2 action, inhibited PKC activity. These results suggest that 24,25-(OH)2D3 regulates PKC activity by two distinct phospholipid-dependent mechanisms: production of DAG via phospholipase D and inhibition of the production of PGE2 via inhibition of phospholipase A2 and cyclooxygenase.
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PMID:24,25-(OH)2D3 regulates protein kinase C through two distinct phospholipid-dependent mechanisms. 895

Phospholipase A2 (PLA2) is an enzyme which participates in signalling mechanisms cleaving arachidonate from sn-2 position of glycerophospholipids. In this study we have verified the existence of a PLA2-like activity in the free living protozoan, Tetrahymena pyriformis GL. This activity is Ca(2+)-independent, EDTA (10 mM) has no effect on its activity. Quinacrine (0.1 mM) and 4-bromophenacyl bromide (BPB; 0.1 mM) inhibited, melittin (20 micrograms/ml) significantly stimulated the PLA2 activity and the release of free arachidonic acid (AA) from 1-acyl 2-14C-arachidonyl-3-phosphatidylethanolamine substrate. Melittin stimulated PLA2 hyperactivity is CA(2+)-dependent. There was no considerable alteration in the PLA2 activity by stimulation of the activity by tyrosine kinase (with vanadate, H2O2), phospholipase C (PLC) (with phorbol 12, 13-dibutyrate) or G-proteins (with NaF, AlF4), thus in Tetrahymena PLA2 activity seems to be independent of these--in Tetrahymena (also functioning)--signalling pathways. Treatment with quinacrine and BPB leads to decreased synthesis and disturbed breakdown of phospholipids and phosphoinositides. These findings suggest that PLA2 activity is in connection with the phospholipid metabolism of Tetrahymena.
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PMID:PLA2 activity in Tetrahymena pyriformis. Effects of inhibitors and stimulators. 904 74

[Arg8]vasopressin (AVP), through its V1 receptor coupled to GTP-binding proteins, and aluminum fluoride (AlF4-), which directly activates GTP-binding proteins, induced the release of [3H]arachidonate from prelabeled A7r5 vascular smooth muscle-like cells. Using fura-2-loaded cells, we observed that the release induced by AVP occurred concurrently with calcium (Ca2+) mobilization from internal stores and entry of external Ca2+, whereas AlF4(-)-dependent arachidonate release was much slower and was not accompanied by intracellular Ca2+ mobilization. Arachidonate transfer from phosphatidylcholine to phosphatidylethanolamine was an early event for both agonists, but phosphatidylinositol hydrolysis was an early event for AVP-stimulated cells and a late event for cells triggered with AlF4-. In addition, phospholipase inhibitors had no effect on arachidonate release induced by AlF4-. We investigated the enzymatic pathways involved in the releases of arachidonate, which occur in such different ways. Phospholipase A2 activities were assayed in a cell-free system with various substrates, which made it possible to differentiate between cytosolic, secretory and Ca2(+)-independent phospholipases A2. The specific activities were in the order alkenyl-AA-GPE > acyl-AA-GPE > acyl-AA-GPC in the presence of Ca2+. No significant activity was observed in the presence of Ca2+ chelators and when dipalmitoyl-glycerophosphocholine was used as a substrate. Phospholipase A2 activities did not change in homogenates from stimulated cells related to control cells. However, phospholipase A2 activity increased in membrane fractions from AVP-stimulated cells. Imunodetected phosphorylated and unphosphorylated forms of cytosolic phospholipase A2 (cPLA2) also clearly increased in the membrane fractions of AVP-stimulated cells, and only the unphosphorylated form of cPLA2 was present in AlF4(-)-triggered cells. We conclude that phospholipase C and translocation of cPLA2 can account for arachidonate release with AVP stimulation, whereas neither phospholipase C nor any phospholipase A2 activity appears to be implicated in AlF4(-)-dependent arachidonate release.
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PMID:Phospholipase A2-dependent and -independent pathways of arachidonate release from vascular smooth muscle cells. 906 36

We have previously shown that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) plays a major role in growth zone chondrocyte (GC) differentiation and that this effect is mediated by protein kinase C (PKC). The aim of the present study was to identify the signal transduction pathway used by 1,25(OH)2D3 to stimulate PKC activation. Confluent, fourth passage GC cells from costochondral cartilage were used to evaluate the mechanism of PKC activation. Treatment of GC cultures with 1,25(OH)2D3 elicited a dose-dependent increase in both inositol-1,4,5-trisphosphate and diacylglycerol (DAG) production, suggesting a role for phospholipase C and potentially for phospholipase D. Addition of dioctanoylglycerol to plasma membranes isolated from GCs increased PKC activity. Neither pertussis toxin nor choleratoxin had an inhibitory effect on PKC activity in control or 1,25(OH)2D3-treated GCs, indicating that neither Gi nor Gs proteins were involved. Phospholipase A2 inhibitors, quinacrine, OEPC (selective for secretory phospholipase A2), and AACOCF3 (selective for cytosolic phospholipase A2), and the cyclooxygenase inhibitor indomethacin decreased PKC activity, while the phospholipase A2 activators melittin and mastoparan increased PKC activity in GC cultures. Arachidonic acid and prostaglandin E2, two downstream products of phospholipase A2 action, also increased PKC activity. These results indicate that 1,25(OH)2D3-dependent stimulation of PKC activity is regulated by two distinct phospholipase-dependent mechanisms: production of DAG, primarily via phospholipase C and production of arachidonic acid via phospholipase A2.
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PMID:1,25(OH)2D3 regulates protein kinase C activity through two phospholipid-dependent pathways involving phospholipase A2 and phospholipase C in growth zone chondrocytes. 955 56

The contributions of several Ca(2+)-dependent processes to neurotoxicity were examined in primary cultures of rat cortical neurons. The Ca2+ ionophore ionomycin induced a rapid loss of axonal morphology and concomitant release of inositol phosphates that preceded morphological alterations of neuronal cell bodies, choline and arachidonate release, and protein degradation. These events were followed by a degree of neuronal lysis proportional to the external Ca2+ concentration and exposure time. The phospholipase inhibitor neomycin decreased both arachidonate release and the phospholipid hydrolysis catalysed by phospholipases C and D. Proteolysis was abated by the protease inhibitor leupeptin, but not by lysosomal proteolysis inhibitors. Neuronal lysis was inhibited partially by either leupeptin or neomycin and almost completely by both in combination. However, neither agent, alone or in combination, affected the morphological derangements. The diacylglycerol lipase inhibitor RHC-80267 reduced arachidonate release, but not neuronal lysis. Phospholipase A2 inhibitors had no effect on either arachidonate release or lysis. Treatment of mixed cultures of neurons and glia with a Ca(2+)-dependent glutamate challenge caused similar morphological changes and a delayed neuronal lysis that was also diminished by leupeptin and neomycin, but not by inhibitors of lysosomal proteolysis. These data describe several distinct stages of Ca(2+)-dependent injury to cortical neurons, a key feature of which is the stimulation of protease, and phospholipase C and D activities. The initial stage is characterized by a rapid loss of axonal morphology and increased phosphatidylinositol hydrolysis. An intermediate stage involves changes in cell body morphology plus the degradation of neuronal protein and phosphatidylcholine. In a later stage, the loss of plasma membrane integrity denotes neuronal death.
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PMID:Ca(2+)-dependent mechanisms of cell injury in cultured cortical neurons. 969 20

During fertilization the spermatozoon undergoes a process of regulated exocytosis triggered by oocyte-associated agonists. An early response generated by agonist-receptor interaction in spermatozoa is the activation of mechanisms leading to Ca2+ influx, this ion being essential for the activation of phospholipases and for the fusion of the plasma membrane with the outer acrosomal membrane. Both a phosphoinositide-specific, and a phosphatidylcholine-specific phospholipase C are involved in the generation of a variety of diacylglycerol molecular species. Phospholipase D, on the other hand, does not seem to contribute (together with a phosphatidate phosphohydrolase) to a significant generation of diacylglycerol. Phospholipase A2 action serves to release fatty acids and to generate lysophospholipids that, either directly or serving as substrates for the generation of other metabolites, have and essential role in the final stages of membrane fusion. Additional work needs to be carried out in the future to characterize which phospholipase isoenzymes are present in mammalian spermatozoa and mechanisms regulating these enzymes
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PMID:Role of phospholipases during sperm acrosomal exocytosis. 979 2


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