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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein kinase C (PKC) activator 12-O-tetradecanoylphorbol 13-acetate (TPA) has been shown to potentiate the stimulatory effect of ethanol on the hydrolysis of phosphatidylethanolamine (PtdEtn) in NIH 3T3 fibroblasts. Following an initial 20-min period, the main product of PtdEtn degradation in cells treated with TPA plus ethanol was ethanolamine phosphate. Here, we have examined the regulatory role of PKC and the possible catalytic role of phospholipase C in the formation of ethanolamine phosphate. TPA, bryostatin, and bombesin, direct or indirect activators of PKC, had similar potentiating effects on ethanol-induced formation of [14C]ethanolamine phosphate from [14C]PtdEtn in [14C]ethanolamine-prelabelled NIH 3T3 fibroblasts. At lower concentrations of ethanol (40-80 mM), significant stimulation of ethanolamine phosphate formation required longer treatments (2 h or longer). The combined effects of TPA (100 nM) and ethanol (50-200 mM) on ethanolamine phosphate formation were not inhibited by the PKC inhibitors staurosporine or 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7). In contrast, these inhibitors significantly inhibited TPA-induced formation of ethanolamine, catalyzed by a phospholipase-D-type enzyme. In membranes isolated from TPA+ethanol-treated cells, enhanced formation of ethanolamine phosphate was maintained for at least 20 min. Down-regulation of PKC by prolonged (24-h) treatment of NIH 3T3 fibroblasts by 300 nM TPA enhanced, while overexpression of alpha-PKC in Balb/c fibroblasts diminished, the stimulatory effect of ethanol on the formation of ethanolamine phosphate. Finally, addition of the protein phosphatase inhibitor okadaic acid (2 microM) to fibroblasts inhibited TPA+ethanol-induced formation of ethanolamine phosphate. These results suggest that alpha-PKC-mediated protein phosphorylation may negatively regulate PtdEtn hydrolysis and that the potentiating effect of TPA may result, at least partly, from increased degradation of this PKC isoform.
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PMID:The long-term combined stimulatory effects of ethanol and phorbol ester on phosphatidylethanolamine hydrolysis are mediated by a phospholipase C and prevented by overexpressed alpha-protein kinase C in fibroblasts. 132 80

The possibility of an insulin-independent blood glucose decreasing activity of sulfonylureas was re-evaluated. Single dose studies in dogs with different sulfonylureas revealed a ranking in the ratio of plasma insulin release/blood glucose decrease with glimepiride exhibiting the lowest and glibenclamide the highest ratio. This ranking suggests that sulfonylureas have extrapancreatic activity and that this is most pronounced for glimepiride. Further evidence for this was derived from single dose studies in rabbits, euglycemic hyperinsulinemic clamp studies in rats and subchronic studies in manifestly diabetic KK-AY mice. Extrapancreatic activity of sulfonylureas as deduced from the ranking in vivo between glimepiride and glibenclamide directly on peripheral tissues would imply a similar ranking between the two drugs in glucose utilizing processes in isolated muscle and fat cells. Indeed, glimepiride exhibits a higher potency compared to glibenclamide with respect to stimulation of glucose transport, glucose transporter isoform 4 (GLUT4) translocation and lipid and glycogen synthesis in normal and insulin-resistant adipocytes and in muscle cells, as well as of the potential underlying signalling processes examined at the molecular level. The molecular basis for the sulfonylurea-induced increase of glucose transport and non-oxidative glucose metabolism may rely on the dephosphorylation of key metabolic proteins/enzymes, like GLUT4 as demonstrated in isolated rat adipocytes. Activation of certain serine/threonine-specific protein phosphatases by insulin has been postulated to be mediated by the mitogen-activated protein kinase (MAPK) pathway and phosphatidylinositol (P1)-3'-kinase. However, there was no evidence that these pathways are involved in the regulation of protein phosphatase activity by sulfonylureas. Binding and photoaffinity studies showed that glimepiride associates in a time- and concentration dependent non-saturable manner with detergent-insoluble complexes of the plasma membrane which may correspond to caveolae. This association seems to be based on the interaction of glimepiride with glycosyl-phosphatidylinositol (GPI) lipids and membrane protein anchors. These were found to be enriched in detergent-insoluble complexes together with a GPI-specific phospholipase (PLC), the caveolae-specific coast protein, caveolin, and acylated tyrosine kinases of the src family. Sulfonylureas were found to stimulate the GPI-PLC and tyrosine phosphorylation of caveolin. This is presumably caused by direct interaction of the sulfonylurea into caveolar glycolipids and stimulation of a caveolar src tyrosine kinase, respectively. In accordance with the higher potency of glimepiride in vivo and in glucose transport/metabolism in vitro, the EC50 values for GPI-PLC activation and caveolin phosphorylation were lower for glimepiride than those for glibenclamide. The stimulation of protein tyrosine phosphorylation by sulfonylureas via this pathway not involving the insulin signaling cascade may be coupled to activation of specific protein phosphatases regulating glucose transport and metabolism. The concentrations required in vitro were higher than the reported therapeutic plasma concentrations. However, provided that the observed time-dependent accumulation of glimepiride in caveolae of peripheral cells were of functional relevance for stimulation of glucose transport/metabolism and would also occur in vivo, due to the longer exposure times even at lower drug concentrations the insulin-independent blood glucose decreasing activity of sulfonylureas might become effective in vivo.
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PMID:Characterization of the molecular mode of action of the sulfonylurea, glimepiride, at adipocytes. 891 85

Platelet-derived growth factor (PDGF) stimulates protein kinase D (PKD) in a time- and dose-dependent manner. We have used a series of PDGF receptor mutants that display a selective impairment of the binding of SH2-containing proteins (GTPase-activating protein, SHP-2, phospholipase Cgamma (PLCgamma), or phosphatidylinositol 3'-kinase (PI3K)) to show that Tyr-1021, the PLCgamma-binding site, is essential for PKD stimulation by PDGF in A431 cells. We next investigated whether any one of these four binding sites could mediate PKD activation in the absence of the other three sites. F5, a receptor mutant that lacks all four binding sites for GTPase-activating protein, PLCgamma, PI3K, and SHP-2, fails to activate PKD. A panel of single add-back mutants was used to investigate if any one of these four sites could restore signaling to PKD. Of the four sites, only the PLCgamma+ single add-back receptor restored PDGF-mediated activation of PKD, and only this add-back receptor produced diacylglycerol (DAG) in a PDGF-dependent manner. 1,2-Dioctanoyl-sn-glycerol, a membrane-permeant DAG analog, was found to be sufficient for activation of PKD. Taken together, these data indicate that PLCgamma activation is not only necessary, but also sufficient to mediate PDGF-induced PKD activation. Although the presence of a pleckstrin homology domain makes PKD a potential PI3K target, PKD was not stimulated by selective PI3K activation, and wortmannin, an inhibitor of PI3K, did not inhibit PDGF signaling to PKD. The activation of PKD by DAG or by the wild-type and PLCgamma+ add-back PDGF receptors was inhibited by GF109203X, suggesting a role for protein kinase C in the stimulation of PKD by PDGF. PDGF induced a time-dependent phosphorylation of PKD that closely correlated with activation. The PDGF-induced activation and phosphorylation of PKD were reversed by in vitro incubation of PKD with protein phosphatase 1 or 2A, indicating that PDGF signaling to PKD involves the Ser/Thr phosphorylation of PKD. Taken together, these results conclusively show that PDGF activates PKD through a pathway that involves activation of PLCgamma and, subsequently, protein kinase C.
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PMID:Platelet-derived growth factor stimulates protein kinase D through the activation of phospholipase Cgamma and protein kinase C. 950 12

Biological processes involving light may have both beneficial (photosynthesis) and destructive (photosensitization) consequences. Singlet molecular oxygen, (1)O2, and other reactive oxygen species such as hydrogen peroxide and hydroxyl radical, arise during the interaction of light with photosensitizing chemicals in the presence of molecular oxygen. (1)O2 oxidizes macromolecules such as lipids, nucleic acids, and protein, depending on its intracellular site of formation; and promotes detrimental processes such as lipid peroxidation, membrane damage, and cell death. Photochemical reactive oxygen species (ROS) generating systems induce the expression of several eukaryotic genes, which include stress proteins, early response genes, matrix metalloproteinases, immunomodulatory cytokines, and adhesion molecules. These gene expression phenomena may belong to cellular defensive mechanisms, or may promote further injury. Whereas the signal transduction pathways that link site-specific oxidative damage and gene expression are poorly understood, ROS may affect signalling components in the membrane, cytosol, or nucleus, leading to changes in phospholipase, cyclooxygenase, protein kinase, protein phosphatase, and transcription factor activities. Limited evidence for (1)O2 involvement in gene activation phenomena consists of deuterium oxide solvent effects, inhibition by (1)O2-quenchers, sensitization by porphyrins, chemical trapping methods, and comparative effects of photosensitizing dyes and thermolabile endoperoxides. The studies outlined in this review support an hypothesis that (1)O2 and other ROS generated during photochemical processes such as ultraviolet-A (320-380 nm) radiation exposure, or photosensitizer mediated oxidation may have dramatic effects on eukaryotic gene expression.
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PMID:Singlet molecular oxygen ((1)O2): a possible effector of eukaryotic gene expression. 964 Dec 71

Cardiac hypertrophy and dilatation can result from stimulation of signal transduction pathways mediated by heterotrimeric G proteins, especially Gq, whose alpha subunit activates phospholipase Cbeta (PLCbeta). We now report that transient, modest expression of a hemagglutinin (HA) epitope-tagged, constitutively active mutant of the Gq alpha subunit (HAalpha*q) in hearts of transgenic mice is sufficient to induce cardiac hypertrophy and dilatation that continue to progress after the initiating stimulus becomes undetectable. At 2 weeks, HAalpha*q protein is expressed at less than 50% of endogenous alphaq/11, and the transgenic hearts are essentially normal morphologically. Although HAalpha*q protein declines at 4 weeks and is undetectable by 10 weeks, the animals develop cardiac hypertrophy and dilatation and die between 8 and 30 weeks in heart failure. As the pathology develops, endogenous alphaq/11 rises (2.9-fold in atria; 1.8-fold in ventricles). At 2 weeks, basal PLC activity is increased 9- to 10-fold in atria but not ventricles. By 10 weeks, it is elevated in both, presumably because of the rise in endogenous alphaq/11. We conclude that the pathological changes initiated by early, transient HAalpha*q expression are maintained in part by compensatory changes in signal transduction and other pathways. Cyclosporin A (CsA) prevents hypertrophy caused by activation of calcineurin [Molkentin, J. D., Lu, J.-R., Antos, C. L., Markham, B., Richardson, J., Robbins, J., Grant, S. R. & Olson, E. N. (1998) Cell 93, 215-228]. Because HAalpha*q acts upstream of calcineurin, we hypothesized that HAalpha*q might initiate additional pathways leading to hypertrophy and dilatation. Treating HAalpha*q mice with CsA diminished some, but not all, aspects of the hypertrophic phenotype, suggesting that multiple pathways are involved.
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PMID:Transient cardiac expression of constitutively active Galphaq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways. 981 97

In the Drosophila visual cascade, the transient receptor potential (TRP) calcium channel, phospholipase Cbeta (no-receptor-potential A), and an eye-specific isoform of protein kinase C (eye-PKC) comprise a multimolecular signaling complex via their interaction with the scaffold protein INAD. Previously, we showed that the interaction between INAD and eye-PKC is a prerequisite for deactivation of a light response, suggesting eye-PKC phosphorylates proteins in the complex. To identify substrates of eye-PKC, we immunoprecipitated the complex from head lysates using anti-INAD antibodies and performed in vitro kinase assays. Wild-type immunocomplexes incubated with [(32)P]ATP revealed phosphorylation of TRP and INAD. In contrast, immunocomplexes from inaC mutants missing eye-PKC, displayed no phosphorylation of TRP or INAD. We also investigated protein phosphatases that may be involved in the dephosphorylation of proteins in the complex. Dephosphorylation of TRP and INAD was partially suppressed by the protein phosphatase inhibitors okadaic acid, microcystin, and protein phosphatase inhibitor-2. These phosphatase activities were enriched in the cytosol of wild-type heads, but drastically reduced in extracts prepared from glass mutants, which lack photoreceptors. Our findings indicate that INAD functions as RACK (receptor for activated PKC), allowing eye-PKC to phosphorylate INAD and TRP. Furthermore, dephosphorylation of INAD and TRP is catalyzed by PP1/PP2A-like enzymes preferentially expressed in photoreceptor cells.
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PMID:Reversible phosphorylation of the signal transduction complex in Drosophila photoreceptors. 1076 55

The ppb1(+) gene encodes a fission yeast homologue of the mammalian calcineurin. We have recently shown that Ppb1 is essential for chloride ion homeostasis, and acts antagonistically with Pmk1 mitogen-activated protein kinase pathway. In an attempt to identify genes that share an essential function with calcineurin, we screened for mutations that confer sensitivity to the calcineurin inhibitor FK506 and high temperature, and isolated a mutant, its3-1. its3(+) was shown to be an essential gene encoding a functional homologue of phosphatidylinositol-4-phosphate 5-kinase (PI(4)P5K). The temperature upshift or addition of FK506 induced marked disorganization of actin patches and dramatic increase in the frequency of septation in the its3-1 mutants but not in the wild-type cells. Expression of a green fluorescent protein-tagged Its3 and the phospholipase Cdelta pleckstrin homology domain indicated plasma membrane localization of PI(4)P5K and phosphatidylinositol 4,5-bisphosphate. These green fluorescent protein-tagged proteins were concentrated at the septum of dividing cells, and the mutant Its3 was no longer localized to the plasma membrane. These data suggest that fission yeast PI(4)P5K Its3 functions coordinately with calcineurin and plays a key role in cytokinesis, and that the plasma membrane localization of Its3 is the crucial event in cytokinesis.
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PMID:Phosphatidylinositol 4-phosphate 5-kinase Its3 and calcineurin Ppb1 coordinately regulate cytokinesis in fission yeast. 1095 Sep 58

We recently reported that leukemia inhibitory factor (LIF) enhances Ca(2+)](i) through an increase in L-type Ca(2+) current (I(Ca,L)) in adult cardiomyocytes. The aim of this study was to investigate whether LIF activates Ca(2+)-dependent signaling molecules, such as calcineurin and calmodulin kinases II and IV (CaMKII and CaMKIV), and, if so, whether these Ca(2+)-mediated signaling events contribute to LIF-mediated cardiac hypertrophy. We first confirmed that LIF increased I(Ca,L) and [Ca(2+)](i) in primary cultured rat neonatal cardiomyocytes. Calcineurin, CaMKII, and CaMKIV activities increased at 2 minutes and peaked by 1.6-, 2.2-, and 2.2-fold, respectively, at 15 minutes. Nicardipine or verapamil fully inhibited these activities. Autophosphorylation of CaMKII was also observed to parallel the timing of CaMKII activity, and this phosphorylation was blocked by nicardipine, verapamil, or EGTA. LIF treatment led to a 3-fold increase in nuclear factor of activated T cell-luciferase activity. To confirm that inositol triphosphate (IP(3))-induced Ca(2+) release from sarcoplasmic reticulum was not involved in this process, IP(3) content and phosphorylation of phospholipase Cgamma were investigated. LIF did not increase IP(3) content or phosphorylate phospholipase Cgamma. KN62 (an inhibitor of CaMKII and CaMKIV) attenuated c-fos, brain natriuretic peptide, alpha-skeletal actin, and atrial natriuretic peptide expression. KN62 suppressed the LIF-induced increase in [(3)H]phenylalanine uptake and cell size. Cyclosporin A and FK506 slightly attenuated brain natriuretic peptide but did not affect c-fos or atrial natriuretic peptide expression. Cyclosporin A significantly reduced the LIF-induced increase in [(3)H]phenylalanine uptake. These findings indicated that LIF activated CaMKII, CaMKIV, and calcineurin through an increase in I:(Ca,L) and [Ca(2+)](i) and that CaMKII, CaMKIV, and calcineurin are critically involved in LIF-induced cardiac hypertrophy.
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PMID:Calmodulin kinases II and IV and calcineurin are involved in leukemia inhibitory factor-induced cardiac hypertrophy in rats. 1107 91

Muscarinic acetylcholine receptors in NG108-15 neuroblastoma x glioma cells, and beta-adrenergic or angiotensin II receptors in cortical astrocytes and/or ventricular myocytes, utilize the direct signaling pathway to ADP-ribosyl cyclase within cell membranes to produce cyclic ADP-ribose (cADPR) from beta-NAD+. This signal cascade is analogous to the previously established transduction pathways from bradykinin receptors to phospholipase Cbeta and beta-adrenoceptors to adenylyl cyclase via G proteins. Upon receptor stimulation, the newly-formed cADPR may coordinately function to upregulate the release of Ca2+ from the type II ryanodine receptors as well as to facilitate Ca2+ influx through voltage-dependent Ca2+ channels. cADPR interacts with FK506, an immunosuppressant, at FKBP12.6, FK506-binding-protein, and calcineurin, or ryanodine receptors. cADPR also functions through activating calcineurin released from A-kinase anchoring protein (AKAP79). Thus, some G(q/11)-coupled receptors can control cADPR-dependent modulation in Ca2+ signaling.
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PMID:Signal transduction from bradykinin, angiotensin, adrenergic and muscarinic receptors to effector enzymes, including ADP-ribosyl cyclase. 1125 66

Fc(epsilon)RI-induced Ca2+ signaling in mast cells is initiated by activation of cytosolic tyrosine kinases. Here, in vitro phospholipase assays establish that the phosphatidylinositol 3-kinase (PI 3-kinase) lipid product, phosphatidylinositol 3,4,5-triphosphate, further stimulates phospholipase Cgamma2 that has been activated by conformational changes associated with tyrosine phosphorylation or low pH. A microinjection approach is used to directly assess the consequences of inhibiting class IA PI 3-kinases on Ca2+ responses after Fc(epsilon)RI cross-linking in RBL-2H3 cells. Injection of antibodies to the p110beta or p110delta catalytic isoforms of PI 3-kinase, but not antibodies to p110alpha, lengthens the lag time to release of Ca2+ stores and blunts the sustained phase of the calcium response. Ca2+ responses are also inhibited in cells microinjected with recombinant inositol polyphosphate 5-phosphatase I, which degrades inositol 1,4,5-trisphosphate (Ins(1,4,5)P3), or heparin, a competitive inhibitor of the Ins(1,4,5)P3 receptor. This indicates a requirement for Ins(1,4,5)P3 to initiate and sustain Ca2+ responses even when PI 3-kinase is fully active. Antigen-induced cell ruffling, a calcium-independent event, is blocked by injection of p110beta and p110delta antibodies, but not by injection of 5-phosphatase I, heparin, or anti-p110alpha antibodies. These results suggest that the p110beta and p110delta isoforms of PI 3-kinase support Fc(epsilon)RI-induced calcium signaling by modulating Ins(1,4,5)P3 production, not by directly regulating the Ca2+ influx channel.
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PMID:p110beta and p110delta phosphatidylinositol 3-kinases up-regulate Fc(epsilon)RI-activated Ca2+ influx by enhancing inositol 1,4,5-trisphosphate production. 1127 65


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