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)

A number of studies have reported that the activity of the ryanodine-sensitive calcium release channel (ryanodine receptor) in the junctional sarcoplasmic reticulum of skeletal and cardiac muscle can be modulated by protein phosphorylation-dephosphorylation through activation of endogenous protein kinases and/or by addition of exogenous protein kinases and protein phosphatases. In this study, we have investigated the possibility that protein phosphatase-1 (PP1) is targeted to the junctional sarcoplasmic reticulum by the direct isolation of PP1-binding proteins on PP1-Sepharose affinity columns. The results show that the ryanodine receptor of both skeletal and cardiac muscle bind to this affinity support, and are released at supraphysiological salt concentrations in a relatively pure state. Reciprocal experiments demonstrated that PP1 binds to the immobilized muscle ryanodine receptor. The direct binding of PP1 to the ryanodine receptor was supported by the finding that tryptic fragments of the receptor were retained on PP1-Sepharose. The ability of PP1 to dephosphorylate the ryanodine receptor that was phosphorylated by protein kinase A was also demonstrated. These studies show that PP1 is targeted to the junctional sarcoplasmic reticulum by binding to the ryanodine receptor, and provide a biochemical basis for the possibility that PP1 may play a role in the regulation of calcium flux via protein phosphorylation-dephosphorylation mechanisms.
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PMID:Binding of the catalytic subunit of protein phosphatase-1 to the ryanodine-sensitive calcium release channel protein. 992 79

The regulatory subunit of S. cerevisiae casein kinase II (CKII) is encoded of two genes, CKB1 and CKB2. Strains harboring deletions of either or both genes exhibit specific sensitivity to high concentrations of Na+ or Li+. Na+ tolerance in S. cerevisiae is mediated primarily by transcriptional induction of ENA1, which encodes the plasma membrane sodium pump, and by conversion of the potassium uptake system to a higher affinity form that discriminates more efficiently against Na+. To determine whether reduced ENA1 expression plays a role in the salt sensitivity of ckb mutants, we integrated an ENA1-lacZ reporter gene into isogenic wild-type, ckb1, ckb2, and ckb1 ckb2 strains and monitored beta-galactosidase activity at different salt concentrations. In all three mutants transcription from the ENA1 promoter remained salt-inducible, but both basal and salt-induced expression was depressed approximately 3- to 4-fold. The degree of reduction in ENA1 expression was comparable to that observed in an isogenic strain carrying a null mutation in protein phosphatase 2B (calcineurin), which is also required for salt tolerance. These results suggest that reduced expression ofENA1 contributes to the salt sensitivity of ckb strains. Consistent with this conclusion, overexpression of ENA1 from a heterologous promoter (GAL1) completely suppressed the salt sensitivity of ckb mutants. Induction of ENA1 expression by alkaline pH is also depressed in ckb mutants, but unlike calcineurin mutants, ckb strains are not growth inhibited by alkaline pH.
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PMID:Transcriptional regulation of the S. cerevisiae ENA1 gene by casein kinase II. 1009 5

The target of the immunosuppressants cyclosporin A(CsA) and FK506 is calcineurin, a highly conserved protein phosphatase that is required for T-cell activation and the regulation of ion homeostasis in yeast. Here we identify two genes, PMR2B and LIC4 which, when overexpressed, suppress the cation-sensitive phenotype of yeast cells lacking calcineurin. PMR2B encodes a Na+/Li+-specific plasma membrane pump and is similar to PMR2A, whose expression is known to be regulated by calcineurin. LIC4 (lithium comvertas) encodes a novel 33-kDa protein with no identity to known proteins. LIC4 overexpression suppresses the Li+-sensitive phenotype of calcineurin mutants but not the defect in recovery from pheromone arrest or viability of calcineurin dependent mutants, indicating a specific role in cation homeostasis. Similarly, lic4 mutations increase the Li+ sensitivity of both wild-type and calcineurin mutant strains, and reduce expression of pmr2A in calcineurin mutant strains, indicating that calcineurin and Lic4 may regulate parallel cation homeostatic pathways. lic4 mutations also exacerbate the Li+-sensitive phenotype of hal3 mutant strains, and overexpression of either Lic4 or Hal3 suppresses the salt sensitivity of mutant strains lacking calcineurin, Hal3, or Lic4, either singly or in combination. Taken together, these observations suggest that calcineurin, Hal3, and Lic4 cooperatively regulate the response of yeast cells to cation stress. Lic4 is phosphoprotein in vivo and a calcineurin substrate in vitro. By indirect and direct immunofluorescence detection of HA- and GFP-tagged proteins, Lic4 is localized in the nucleus in wild-type cells but predominantly cytoplasmic in cells lacking calcineurin. Taken together, our findings support a model in which calcineurin and Lic4 are components of signalling cascades that regulate cation stress responses in yeast.
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PMID:Lic4, a nuclear phosphoprotein that cooperates with calcineurin to regulate cation homeostasis in Saccharomyces cerevisiae. 1010 75

An important effector of Ca2+ signaling in animals and yeast is the Ca2+/calmodulin-dependent protein phosphatase calcineurin. However, the biochemical identity of plant calcineurin remained elusive. Here we report the molecular characterization of AtCBL (Arabidopsis thaliana calcineurin B-like protein) from Arabidopsis. The protein is most similar to mammalian calcineurin B, the regulatory subunit of the phosphatase. AtCBL also shows significant similarity with another Ca2+-binding protein, the neuronal calcium sensor in animals. It contains typical EF-hand motifs with Ca2+-binding capability, as confirmed by in vitro Ca2+-binding assays, and it interacts in vivo with rat calcineurin A in the yeast two-hybrid system. Interaction of AtCBL1 and rat calcineurin A complemented the salt-sensitive phenotype in a yeast calcineurin B mutant. Cloning of cDNAs revealed that AtCBL proteins are encoded by a family of at least six genes in Arabidopsis. Genes for three isoforms were identified in this study. AtCBL1 mRNA was preferentially expressed in stems and roots and its mRNA levels strongly increased in response to specific stress signals such as drought, cold, and wounding. In contrast, AtCBL2 and AtCBL3 are constitutively expressed under all conditions investigated. Our data suggest that AtCBL1 may act as a regulatory subunit of a plant calcineurin-like activity mediating calcium signaling under certain stress conditions.
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PMID:Genes for calcineurin B-like proteins in Arabidopsis are differentially regulated by stress signals. 1020 Feb 39

Yeast cells respond to a shift to higher osmolarity by increasing the cellular content of the osmolyte glycerol. This response is accompanied by a stimulation of the expression of genes encoding enzymes in the glycerol production pathway. In this study the osmotic induction of one of those genes, GPD1, which encodes glycerol-3-phosphate dehydrogenase, was monitored in time course experiments. The response is independent of the osmolyte and consists of four apparent phases: a lag phase, an initial induction phase, a feedback phase and a sustained long-term induction. Osmotic shock with progressively higher osmolyte concentrations caused a prolonged lag phase. Deletion of HOG1, which encodes the terminal protein kinase of the high osmolarity glycerol (HOG) response pathway, led to an even longer lag phase and drastically lower basal and induced GPD1 mRNA levels. However, the induction was only moderately diminished. Overstimulation of Hog1p by deletion of the genes for the protein phosphatases PTP2 and PTP3 led to higher basal and induced mRNA levels and a shorter lag phase. The protein phosphatase calcineurin, which mediates salt-induced expression of some genes, does not appear to contribute to the control of GPD1 expression. Although GPD1 expression has so far not been reported to be controlled by a general stress response mechanism, heat-shock induction of the GPD1 mRNA level was observed. However, unregulated protein kinase A activity, which strongly affects the general stress response, only marginally altered the mRNA level of GPD1. The osmotic stimulation of GPD1 expression does not seem to be mediated by derepression, since deletion of the SSN6 gene, which encodes a general repressor, did not significantly alter the induction profile. A hypoosmotic shock led to a transient 10-fold drop of the GPD1 mRNA level. Neither the HOG nor the protein kinase C pathway, which is stimulated by a decrease in external osmolarity, is involved in this effect. It was concluded that osmotic regulation of GPD1 expression is the result of an interplay between different signalling pathways, some of which remain to be identified.
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PMID:Different signalling pathways contribute to the control of GPD1 gene expression by osmotic stress in Saccharomyces cerevisiae. 1021 6

We recently reported that addition of a small amount of hemolysate to the salt solution that perfused isolated rat lungs hypersensitized the vasculature to subsequent additions of ANG II or exposure to hypoxia, and addition of NO gas (. NO) to the perfusate that contained hemolysate caused a strong vasoconstrictor rather than a vasodilator response. In the present study, we demonstrate that CO and the secondary messengers cGMP and cAMP (usually associated with vasodilation) exert similar effects in hemolysate-perfused lungs. Analogs of the cyclic nucleotides cGMP or cAMP (8-bromo-cGMP and dibutyryl-cAMP, respectively) caused profound vasoconstriction in the isolated rat lung perfused with a salt solution that contained hemolysate. The cGMP- or cAMP-analog-induced vasoconstriction was inhibited by chemically dissimilar Ca2+ antagonists, by the protein phosphatase inhibitor okadaic acid, and, to a lesser degree, by protein kinase inhibitor H-7. Antiphosphothreonine immunoblotting demonstrated that lungs perfused with hemolysate exhibit increased phosphorylation of several proteins. These data indicate that, in the presence of hemolysate, pulmonary vasculature responds to nominally vasodilatory stimuli, including analogs of cGMP and cAMP, with vasoconstriction rather than vasodilation. The importance of our finding is the paradoxical nature of the response to (analogs of) cyclic nucleotides because, to our knowledge, cyclic nucleotide-induced vasoconstriction has not been previously reported.
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PMID:cGMP and cAMP cause pulmonary vasoconstriction in the presence of hemolysate. 1023 39

Saccharomyces cerevisiae cells lacking the regulatory subunit of casein kinase 2 (CK-2), encoded by the gene CKB1, display a phenotype of hypersensitivity to Na(+) and Li(+) cations. The sensitivity of a strain lacking ckb1 is higher than that of a calcineurin mutant and similar to that of a strain lacking HAL3, the regulatory subunit of the Ppz1 protein phosphatase. Genetic analysis indicated that Ckb1 participates in regulatory pathways different from that of Ppz1 or calcineurin. Deletion of CKB1 increased the salt sensitivity of a strain lacking Ena1 ATPase, the major determinant for sodium efflux, suggesting that the function of the kinase is not mediated by Ena1. Consistently, ckb1 mutants did not show an altered cation efflux. The function of Ckb1 was independent of the TRK system, which is responsible for discrimination of potassium and sodium entry, and in the absence of the kinase regulatory subunit, the influx of sodium was essentially normal. Therefore, the salt sensitivity of a ckb1 mutant cannot be attributed to defects in the fluxes of sodium. In fact, in these cells, both the intracellular content and the cytoplasm/vacuole ratio for sodium were similar to those features of wild-type cells. The possible causes for the salt sensitivity phenotype of casein kinase mutants are discussed in the light of these findings.
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PMID:Biochemical and genetic analyses of the role of yeast casein kinase 2 in salt tolerance. 1051 37

The adult kidney has a high rate of dopamine (DA) production, metabolism, and signalling. The non-neuronal DA system in the adult kidney is of utmost importance for the regulation of salt metabolism. DA may also act as a transcription factor and may be of importance for tissue differentiation. In the central nervous system, D1 receptors require the dopamine- and cAMP-regulated phosphoprotein with a molecular weight of 32,000 Dalton (DARPP-32) to mediate their actions. The renal D1 mediates DARPP-32 activation via a cascade involving cAMP and PKA, and protein kinase C (PKC) activation via phospholipase C. Active DARPP-32 has a specific inhibitory effect on protein phosphatase 1 (PP1), leaving, e.g. Na+,K+-ATPase in a phosphorylated, inactive, state. Thus, dopamine acts as a natriuretic hormone in the mature kidney. Here, we discuss the age-dependent distribution and some functional aspects of several parts of the renal dopamine system (dopamine, AADC, COMT, D1 receptor, and DARPP-32) during renal morphogenesis.
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PMID:Dopamine in the developing kidney. 1053 21

Dephosphorylation of central photosynthetic proteins regulates their turnover in plant thylakoid membranes. A membrane protein phosphatase from spinach thylakoids was purified 13000-fold using detergent-engaged FPLC. The purified enzyme exhibited characteristics typical of eukaryotic Ser/Thr phosphatases of the PP2A family in that it was inhibited by okadaic acid (IC(50) = 0.4 nM) and tautomycin (IC(50) = 25 nM), irreversibly bound to microcystin-agarose, and recognized by a polyclonal antibody raised against a recombinant catalytic subunit of human PP2A. Furthermore, the anti-PP2A antibody inhibited protein dephosphorylation in isolated thylakoids. The phosphatase copurified with TLP40, a cyclophilin-like peptidyl-prolyl isomerase located in the thylakoid lumen. TLP40 could be released from the phosphatase immobilized on microcystin-agarose by high-salt treatment. Binding of cyclosporin A (CsA) to TLP40 led to thylakoid phosphatase activation, while cyclophilin substrates, prolyl-containing oligopeptides, inhibited protein dephosphorylation. This dephosphorylation could be modulated by CsA or oligopeptides only after the thylakoids had been ruptured to expose the lumenal membrane surface where the TLP40 is located. Regulation of the PP2A-like phosphatase at the outer thylakoid surface is likely to operate via reversible binding of TLP40 to the inner membrane surface. This is a first example of transmembrane regulation in which the activity of phosphatase is altered by the binding of a cyclophilin to a site other than the active one. We propose that signaling from TLP40 to the protein phosphatase coordinates dephosphorylation and protein folding, two processes required for protein turnover during the repair of photoinhibited photosystem II reaction centers.
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PMID:A cyclophilin-regulated PP2A-like protein phosphatase in thylakoid membranes of plant chloroplasts. 1055 77

Thirty-two protein phosphatase (PPase) genes were identified in the genome nucleotide sequence of Saccharomyces cerevisiae. We constructed S. cerevisiae disruptants for each of the PPase genes and examined their growth under various conditions. The disruptants of six putative PPase genes, i.e. of YBR125c, YCR079w, YIL113w, YJR110w, YNR022c and YOR090c, were created for the first time in this study. The glc7, sit4 and cdc14 disruptants were lethal in our strain background. The remaining 29 PPase gene disruptants were viable at 30 degrees C and 37 degrees C, but only one disruptant, yvh1, showed intrinsic cold-sensitive growth at 13 degrees C. Transcription of the YVH1 gene was induced at 13 degrees C, consistent with an idea that Yvh1p has a specific role for growth at a low temperature. The viable disruptants grew normally on nutrient medium containing sucrose, galactose, maltose or glycerol as carbon sources. The ppz1 disruptant was tolerant to NaCl and LiCl, while the cmp2 disruptant was sensitive to these salts, as reported previously, and none of the other viable PPase disruptants exhibited the salt sensitivity. When the viable disruptants were tested for sensitivity to drugs, i.e. benomyl, caffeine and hydroxyurea, ppz1 and ycr079w disruptants exhibited sensitivity to caffeine.
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PMID:A series of protein phosphatase gene disruptants in Saccharomyces cerevisiae. 1057 63


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