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)

Depolarization can alter the expression of membrane receptors and change certain receptor-mediated events, but previous studies have not assessed the impact of depolarization on generation of arachidonic acid and its metabolites (AA) in nonexcitable tissues. We assessed AA generation in Madin-Darby canine kidney (MDCK) cells grown for 3 days in increased extracellular [K+], which is known to acutely depolarize these cells. Growth under these conditions resulted in decreases in the number of alpha 1-adrenergic receptors (alpha 1 AR), a small decrease in receptor-mediated phosphoinositide hydrolysis, but increases in alpha 1 AR-mediated prostaglandin E2 formation and AA release. Calcium ionophore (A23187)-, melittin-, and bradykinin-stimulated AA release were also enhanced. The reduction in alpha 1 AR number and increased AA release were substantially reduced or eliminated when K(+)-treated cells were grown in the absence of extracellular calcium. The results provide evidence that hormone-stimulated AA release and prostaglandin production can be enhanced by chronic exposure to elevated extracellular K+ concentration, perhaps as a consequence of a depolarization-induced enhancement in phospholipase A2 activity. The results provide evidence for the parallel and independent regulation of the pathways for receptor-mediated phosphoinositide hydrolysis (phospholipase C activation) and AA release (phospholipase A2 activation) in MDCK cells.
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PMID:Elevated extracellular K+ enhances arachidonic acid release in MDCK-D1 cells. 216 33

In the neuroblastoma X glioma hybrid cell line NG108-15, bradykinin (BK) receptor stimulation induced a rapid and concentration-dependent rise in cytosolic free Ca2+ levels, as measured with the Ca2(+)-sensitive fluorescent dye fura-2. The Ca2+ transient was present in the absence of extracellular Ca2+ and was associated with a concentration-dependent production of inositol phosphates, particularly inositol trisphosphate (InsP3). Pretreatment of intact NG108-15 cells with forskolin or dibutyryl-cAMP plus isobutylmethylxanthine reduced BK-stimulated InsP3 production and the increase in cytosolic free Ca2+. Membranes prepared from forskolin- and [3H]inositol-pretreated NG108-15 cells also showed a diminished production of InsP3 elicited by guanosine 5'-[gamma-thio]triphosphate, NaF, or BK plus GTP. On the other hand, the Ca2+ sensitivity of membrane-associated phosphoinositide-specific phospholipase C (PI-PLC) was unaffected by forskolin pretreatment of intact NG108-15 cells. Collectively, these results suggest that A-kinase may inhibit receptor-mediated and postreceptor stimulation of PI-PLC in neuron-like cells, perhaps by impairing the coupling between a guanine nucleotide-binding protein and PI-PLC.
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PMID:Cyclic AMP inhibits inositol polyphosphate production and calcium mobilization in neuroblastoma X glioma NG108-15 cells. 216 7

In this study we investigated the role of protein kinases in activation of the Na(+)-H+ exchanger in inner medullary collecting duct (IMCD) cells. Monolayers, 24-48 h after achieving confluence, were made quiescent by 24 h incubation in 0.1% serum before study. Changes in pHi were measured with 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. Phorbol myristate acetate (PMA), a synthetic analogue of diacylglycerol (DAG), was used to stimulate protein kinase C (PKC). In nominally HCO3(-)-free media containing 110 mM Na+ and 1 mM Ca2+, PMA addition increased pHi from 7.29 +/- 0.08 to 7.54 +/- 0.07 after 20 min. The increment in pHi was completely inhibited by 1 mM amiloride or by replacement of extracellular Na+ with choline but not inhibited by 1 mM N-ethylmaleimide, an inhibitor of active proton transport. Downregulation of PKC by overnight incubation of monolayers with PMA also prevented the rise in pHi upon subsequent challenge with PMA. Another active analogue of DAG, 1,2-dioleoyl-rac-glycerol, caused an increment in pHi similar to that produced by PMA, whereas 4 alpha-phorbol, an inactive analogue, did not stimulate Na(+)-H+ exchange. Bradykinin (10(-6) M), a phospholipase C-activating hormone, also induces alkalinization of IMCD cells similar to that produced by phorbol esters. Neither vasopressin (10(-7) M), which induces cellular accumulation of adenosine 3',5'-cyclic monophosphate (cAMP) and activation of protein kinase A (PKA), nor 8-bromo-cAMP (1 mM) changed pHi. Therefore in the IMCD cell activation of PKC but not PKA stimulates a rise in pHi via the Na(+)-H+ exchanger.
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PMID:Na(+)-H+ exchange is stimulated by protein kinase C activation in inner medullary collecting duct cells. 217 60

Ligand stimulation of the platelet-derived growth factor receptor (PDGF-R) results in rapid activation of the receptor tyrosine kinase, stimulation of phosphoinositide hydrolysis, an increase in intracellular free Ca2+ concentration ([Ca2+]i), and, ultimately, cellular proliferation. In a previous study, we demonstrated that staurosporine, a known inhibitor of protein kinase C, blocked PDGF-induced [Ca2+]i increases in Swiss mouse 3T3 fibroblasts by a mechanism that appeared unrelated to inhibition of protein kinase activity (Olsen, R., Melder, D., Seewald, M., Abraham, R., and Powis, G. (1990) Biochem. Pharmacol. 39, 968-972). In the present study, we report that staurosporine inhibits ligand-dependent PDGF-R tyrosine kinase activation in cell-free receptor preparations and in intact Swiss 3T3 cells. At the same concentrations (10(-8)-10(-6) M), staurosporine suppressed both the tyrosine phosphorylation of phospholipase C activity and the hydrolysis of phosphoinositides induced by PDGF stimulation of intact cells. In contrast, guanine nucleotide-binding protein-dependent phospholipase C activation induced by bradykinin or fluoroaluminate anion was relatively insensitive to staurosporine. A preferential inhibitory effect of staurosporine on signal generation by the PDGF-R was indicated by findings that epidermal growth factor receptor (EGF-R) tyrosine kinase activity and EGF-dependent phospholipase C in A-431 carcinoma cells were approximately 100-fold less sensitive to this drug. These data indicate that submicromolar concentrations of staurosporine inhibit PDGF-dependent phosphoinositide hydrolysis and Ca2+ mobilization through a proximal inhibitory effect on ligand-induced activation of the PDGF-R tyrosine kinase.
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PMID:Preferential inhibition of the platelet-derived growth factor receptor tyrosine kinase by staurosporine. 217 5

The effects of bradykinin on activation of phosphoinositide turnover, 1,2-diglyceride formation, and growth of cultured adult human keratinocytes were investigated. Keratinocytes specifically bound [3H]bradykinin with high affinity (kd = 3.4 nM) and displayed 1.5 X 10(5) binding sites/cell. Bradykinin caused a rapid dose-dependent increase in inositol trisphosphate (IP3) inositol bisphosphate, and inositol monophosphate. IP3 was maximally increased (fivefold) at 30 s and remained elevated for at least 10 min. Half maximal stimulation of IP3 formation was observed at 27 nM bradykinin. IP3 accumulation was equally elevated by bradykinin and lys-bradykinin but was not stimulated by des-Arg9-bradykinin, indicating that phospholipase C in cultured keratinocytes is coupled to B2 bradykinin receptors. Treatment of keratinocytes with active phorbol ester (TPA) caused a significant inhibition (50%) of bradykinin-induced IP3 accumulation, suggesting negative regulation of phospholipase C by protein kinase C. Bradykinin also caused a significant elevation in 1,2-diacylglycerol (DAG) content. DAG content was maximally elevated (twofold) at 1 min and remained elevated for at least 10 min. Bradykinin also caused a significant (twofold, p less than 0.02) increase in keratinocyte growth. These data demonstrate that bradykinin is a potent agonist of the phospholipase C/protein kinase C signal transduction system in cultured adult human keratinocytes and that activation of this pathway by bradykinin is associated with increased keratinocyte growth.
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PMID:Bradykinin induces phosphoinositide turnover, 1,2-diglyceride formation, and growth in cultured adult human keratinocytes. 217 49

The effect of angiotensin II on the cytosolic free Ca2+ concentration was measured in single mouse neuroblastoma N1E-115 cells loaded with fura-2. Angiotensin II induced a transient concentration-dependent increase in Ca2+ and also increased the production of inositol polyphosphates. The Ca2+ increase did not require extracellular Ca2+ and was unaffected by pretreatment with pertussis toxin. These data suggest that angiotensin II increased Ca2+ by an inositol trisphosphate-mediated release of intracellular Ca2+ following activation of phospholipase C via a pertussis toxin-insensitive guanine nucleotide binding protein. Similar results were obtained with bradykinin. The angiotensin II- or bradykinin-induced increase in Ca2+ occurred after a concentration-dependent latent period. Low concentrations of agonist elicited a small increase in Ca2+ following a variable lag that sometimes exceeded 1 min, whereas at maximally effective angiotensin II concentrations a larger, more rapid increase in Ca2+ occurred without a measurable delay. In some cells, oscillatory increases in Ca2+ were induced by angiotensin II and bradykinin. Possible mechanisms to explain the concentration dependency of the latent period and the oscillatory nature of the increases of Ca2+ are discussed. These results indicate that the mouse neuroblastoma N1E-115 cell represents a useful model for studying the signal response transduction mechanisms regulating the effects of angiotensin II in neuronal cells.
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PMID:Angiotensin II effects on the cytosolic free Ca2+ concentration in N1E-115 neuroblastoma cells: kinetic properties of the Ca2+ transient measured in single fura-2-loaded cells. 229 17

Platelet-derived growth factor (PDGF) stimulates phospholipase C (PLC) activity and the phosphorylation of the gamma isozyme of PLC (PLC-gamma) in vitro and in living cells. The role of PLC-gamma in the phosphoinositide signaling pathway was addressed by examining the effect of overexpression of PLC-gamma on cellular responses to PDGF. Overexpression of PLC-gamma correlated with PDGF-induced tyrosine phosphorylation of PLC-gamma and with PDGF-induced breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2). However, neither bradykinin- nor lysophosphatidic acid-induced phosphoinositide metabolism was enhanced in the transfected cells, suggesting that the G protein-coupled phosphoinositide responses to these ligands are mediated by other PLC isozymes. The enhanced PDGF-induced generation of inositol trisphosphate (IP3) did not enhance intracellular calcium signaling or influence PDGF-induced DNA synthesis. Thus, enzymes other than PLC-gamma may limit PDGF-induced calcium signaling and DNA synthesis. Alternatively, PDGF-induced calcium signaling and DNA synthesis may use biochemical pathways other than phosphoinositide metabolism for signal transduction.
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PMID:Effect of phospholipase C-gamma overexpression on PDGF-induced second messengers and mitogenesis. 233 12

Carboxypeptidase M, a plasma membrane-bound enzyme, is present in many human organs and differs from other carboxypeptidase that cleave basic COOH-terminal amino acids. Cultured Madin-Darby canine kidney (MDCK) distal tubular cells contain a kininase I-type enzyme that inactivates bradykinin by releasing Arg9. We found the properties of this kininase to be identical with carboxypeptidase M. In fractionated cells, carboxypeptidase activity sediments with membranes; and detergents, trypsin, and phosphatidylinositol-specific phospholipase C solubilize it, similar to results with human placental carboxypeptidase M. Ten microM 2-mercaptomethyl-3-guanidinoethylthiopropanoic acid and 1 mM o-phenanthroline inhibit, whereas 1.0 mM CoCl2 activates the enzyme. It has a neutral pH optimum and cleaves COOH-terminal Arg or Lys in bradykinin and in shorter peptides. The relative hydrolysis rates of peptides in the presence or absence of 1 mM CoCl2 were similar to those obtained with human carboxypeptidase M. The carboxypeptidase in MDCK cells (54 kDa) cross-reacts with antibodies to human carboxypeptidase M in Western blotting, but not with antibodies to plasma carboxypeptidase N. The enzyme is a glycoprotein; chemical deglycosylation reduced the size to 48 kDa. The presence of the enzyme on the cell membrane of MDCK cells was also shown with transmission electron microscopy using immunogold, which indicated that the enzyme is on the apical side. In addition, MDCK cells contain neutral endopeptidase 24.11 (enkephalinase) and prolylcarboxypeptidase (angiotensinase C) activities. Partitioning of solubilized carboxypeptidase M into Triton X-114 and water indicates that trypsin and phospholipase C remove a hydrophobic tail, while detergent solubilization leaves the hydrophobic moiety intact. Labeling of MDCK cells with [3H]ethanolamine resulted in the synthesis of radiolabeled carboxypeptidase M as determined by immunoprecipitation and fluorography. Thus, MDCK cells contain membrane-bound carboxypeptidase M, which is anchored to the plasma membrane via phosphatidylinositol-glycan. As a major kininase of the distal tubules, it may regulate salt and water excretion.
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PMID:Carboxypeptidase M in Madin-Darby canine kidney cells. Evidence that carboxypeptidase M has a phosphatidylinositol glycan anchor. 239 13

The results of studies to evaluate the hypothesis that the 21 kDa GTP-binding protein derived from the ras oncogene is involved in regulation and coupling of hormone receptors to phospholipase activity have thus far been inconsistent. We therefore examined the effect of H-ras transformation on basal, tumor-promoting phorbol ester (TPA)-stimulated, and bradykinin-mediated phospholipid hydrolysis in Madin Darby canine kidney cells (MDCK) by comparing H-ras-transformed MDCK cells (MDCK-RAS) to two non-transformed strains of MDCK cells (MDCK-D1 and MDCK-ATCC). In unstimulated MDCK-RAS, diacylglycerol (DAG), inositol phosphate accumulation, and choline phosphate release were increased while arachidonic acid and arachidonic acid metabolite (AA) release was not increased, suggesting that ras transformation increased phospholipase C activity. Protein kinase C (PK-C) activity was decreased, and specific binding of [3H]phorbol ester was reduced in MDCK-RAS relative to the non-transformed MDCK cells suggesting that elevated DAG may activate and thereby down-regulate PK-C. Consistent with this finding in MDCK-RAS, TPA-stimulated AA release and subsequent prostaglandin E2 production were decreased, while TPA-stimulated choline phosphate release was increased. Bradykinin receptor-stimulated phospholipid hydrolysis in MDCK-RAS was similar to that of non-transformed cells, suggesting that the ras-derived protein does not directly couple bradykinin receptors to phospholipases in MDCK cells. However, the ability of TPA-treatment to inhibit bradykinin-stimulated phosphoinositide hydrolysis and enhance bradykinin-stimulated AA release was attenuated in MDCK-RAS. Additionally, in MDCK-RAS the conversion of arachidonic acid to prostaglandin E2 was substantially reduced. We conclude that ras transformation of MDCK cells increases DAG levels, thereby activating and, in turn, down-regulating PK-C and certain responses to TPA. Since activation of PK-C may result in a variety of effects on signal transduction pathways, we propose that increased DAG and altered PK-C levels associated with ras transformation may account for the inconsistent effects previously observed in studies evaluating the effect of ras transformation on phospholipases and other signal transduction systems.
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PMID:ras-transformation of MDCK cells alters responses to phorbol ester without altering responses to bradykinin. 240 42

By employing early-passaged rabbit kidney epithelial cells in tissue culture, we demonstrated that angiotensin II (AII) has unique mechanisms of signal transduction. First, unlike its action in other target tissues, micromolar concentrations of AII are required to induce small rises in cytosolic calcium, [Ca2+]i, an action which is not accompanied by the release of inositol phosphates (IP). In contrast, nanomolar bradykinin (BK) mobilizes [Ca2+]i through activation of phospholipase C and release of IP. Neither of these stimulated calcium responses exhibits pertussis toxin (PTx) sensitivity. Secondly, AII and BK at 10(-9) to 10(-7) M stimulate cAMP indirectly through PGE2 production in distal cells. AII- and BK-stimulated PGE2 release is PTx inhibitible, suggestive of the presence of a GTP binding protein mediating the response. By contrast, arginine vasopressin fails to elicit rises in [Ca2+]i but exerts its primary effect on cAMP production in distal cells via direct coupling to a stimulatory GTP binding protein, as evidenced by uncoupling with cholera toxin. Regulation of PGE2 synthesis appears to occur via phospholipase A2, not C, by all three peptides.
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PMID:Relationship between phospholipase C activation and prostaglandin E2 and cyclic adenosine monophosphate production in rabbit tubular epithelial cells. Effects of angiotensin, bradykinin, and arginine vasopressin. 244 59


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