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)

Overexpression of rat recombinant calcineurin A catalytic subunit in E. coli was achieved using a system under control of the T7 promoter. The specific activity of the purified catalytic subunit was suppressed relative to native bovine calcineurin, with the extent of suppression depending upon the choice of substrate. Addition of calcineurin B subunit stimulated phosphatase activity to one third that of native calcineurin. The metal activators Mn2+ and Ni2+ as well as several anion inhibitors affected both native calcineurin and recombinant calcineurin A activity to the same extent. In addition, calcineurin B was required for inhibition by the immunosuppressive complex FK506-FK506-binding protein.
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PMID:Overexpression and characterization of a recombinant form of rat calcineurin A. 751 97

The peptidyl-prolyl isomerases FKBP12 and cyclophilin A (immunophilins) form complexes with the immunosuppressants FK506 and cyclosporin A that inhibit the phosphatase calcineurin. With the yeast two hybrid system, we detect complexes between FKBP12 and the calcineurin A catalytic subunit in both the presence and absence of FK506. Mutations in FKBP12 surface residues or the absence of the calcineurin B regulatory subunit perturb the FK506-dependent, but not the ligand-independent, FKBP12-calcineurin complex. By affinity chromatography, both FKBP12 and cyclophilin A bind calcineurin A in the absence of ligand, and FK506 and cyclosporin A respectively potentiate these interactions. Both in vivo and in vitro, the peptidyl-prolyl isomerase active sites are dispensable for ligand-independent immunophilin-calcineurin complexes. Lastly, by genetic analyses we demonstrate that FKBP12 modulates calcineurin functions in vivo. These findings reveal that immunophilins interact with calcineurin in the absence of exogenous ligands and suggest that immunosuppressants may take advantage of the inherent ability of immunophilins to interact with calcineurin.
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PMID:Immunophilins interact with calcineurin in the absence of exogenous immunosuppressive ligands. 752 75

The immunosuppressive complexes cyclophilin A-cyclosporin A (CsA) and FKBP12-FK506 inhibit calcineurin, a heterodimeric Ca(2+)-calmodulin-dependent protein phosphatase that regulates signal transduction. We have characterized CsA- or FK506-resistant mutants isolated from a CsA-FK506-sensitive Saccharomyces cerevisiae strain. Three mutations that confer dominant CsA resistance are single amino acid substitutions (T350K, T350R, Y377F) in the calcineurin A catalytic subunit CMP1. One mutation that confers dominant FK506 resistance alters a single residue (W430C) in the calcineurin A catalytic subunit CMP2. In vitro and in vivo, the CsA-resistant calcineurin mutants bind FKBP12-FK506 but have reduced affinity for cyclophilin A-CsA. When introduced into the CMP1 subunit, the FK506 resistance mutation (W388C) blocks binding by FKBP12-FK506, but not by cyclophilin A-CsA. Co-expression of CsA-resistant and FK506-resistant calcineurin A subunits confers resistance to CsA and to FK506 but not to CsA plus FK506. Double mutant calcineurin A subunits (Y377F, W388C CMP1 and Y419F, W430C CMP2) confer resistance to CsA, to FK506 and to CsA plus FK506. These studies identify cyclophilin A-CsA and FKBP12-FK506 binding targets as distinct, highly conserved regions of calcineurin A that overlap the binding domain for the calcineurin B regulatory subunit.
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PMID:Targets of immunophilin-immunosuppressant complexes are distinct highly conserved regions of calcineurin A. 754 Sep 76

A complementary DNA for human calcineurin A alpha (protein phosphatase-2B), encoding a protein of 521 amino acids, was isolated from a hippocampus library. The deduced human sequence differs from that of mouse in only two amino acids, demonstrating that the structure of this catalytic subunit has been strictly conserved during mammalian evolution. Such high homology is in contrast to that seen for calcineurin A gamma, an isoform that shows only 88% identity between human and mouse (Muramatsu, T. and Kincaid, R.L. (1992) Biochem. Biophys. Res. Commun. 188, 265-271).
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PMID:Molecular cloning of a full-length cDNA encoding the catalytic subunit of human calmodulin-dependent protein phosphatase (calcineurin A alpha). 839 75

Cyclosporin A (CsA) and FK506 are antimicrobial, immunosuppressive natural products that inhibit signal transduction. In T cells and Saccharomyces cerevisiae, CsA and FK506 bind to the immunophilins cyclophilin A and FKBP12 and the resulting complexes inhibit the Ca2+-regulated protein phosphatase calcineurin. We find that growth of the opportunistic fungal pathogen Cryptococcus neoformans is sensitive to CsA and FK506 at 37 degrees C but not at 24 degrees C, suggesting that CsA and FK506 inhibit a protein required for C. neoformans growth at elevated temperature. Genetic evidence supports a model in which immunophilin-drug complexes inhibit calcineurin to prevent growth at 37 degrees C. The gene encoding the C. neoformans calcineurin A catalytic subunit was cloned and disrupted by homologous recombination. Calcineurin mutant strains are viable but do not survive in vitro conditions that mimic the host environment (elevated temperature, 5% CO2 or alkaline pH) and are no longer pathogenic in an animal model of cryptococcal meningitis. Introduction of the wild-type calcineurin A gene complemented these growth defects and restored virulence. Our findings demonstrate that calcineurin is required for C. neoformans virulence and may define signal transduction elements required for fungal pathogenesis that could be targets for therapeutic intervention.
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PMID:Calcineurin is required for virulence of Cryptococcus neoformans. 918 5

Schizophrenia is a severe psychiatric disorder characterized by a complex mode of inheritance. Forebrain-specific CNB knockout mice display a spectrum of behavioral abnormalities related to altered behaviors observed in schizophrenia patients. To examine whether calcineurin dysfunction is involved in schizophrenia etiology, we undertook studies of an initial subset of calcineurin-related genes, prioritizing ones that map to loci previously implicated in schizophrenia by linkage studies. Transmission disequilibrium studies in a large sample of affected families detected association of the PPP3CC gene, which encodes the calcineurin gamma catalytic subunit, with disease. Our results identify PPP3CC, located at 8p21.3, as a potential schizophrenia susceptibility gene and support the proposal that alterations in calcineurin signaling contribute to schizophrenia pathogenesis.
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PMID:Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. 1285 58

Calcineurin, one of the serine/threonine protein phosphatase, comprises more than 1% of the total protein content in brain. This evidence points towards important roles of calcineurin in neural function. Miyakawa et al. reported that forebrain-specific calcineurin knockout mice showed the behavioral abnormalities that are often observed in schizophrenia patients. Based on this evidence, they suggested that calcineurin dysfunction could be involved in schizophrenia pathogenesis. Thereafter this report, Gerber et al. performed transmission disequilibrium test (TDT) studies and showed an evidence for a nominally significant over-transmission of a common haplotype of the human calcineurin A gamma subunit gene (PPP3CC). We performed association analysis of PPP3CC in Japanese sample of 457 schizophrenia cases and 429 controls. To our regret, we could not confirm the association with Japanese schizophrenia to PPP3CC including core at-risk haplotype. Our result suggests that PPP3CC may not play a major role in Japanese schizophrenia.
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PMID:No association with the calcineurin A gamma subunit gene (PPP3CC) haplotype to Japanese schizophrenia. 1584 70

Calcineurin (protein phosphatase 2B) is a calcium-dependent serine-threonine phosphatase. It has diverse roles and is centrally involved in synaptic plasticity. The catalytic A subunit of calcineurin has three isoforms, alpha, beta and gamma. Their expression and ontogeny in the brain has not been systematically investigated; such data become important with a report that PPP3CC, the gene encoding calcineurin Agamma, is a susceptibility gene for schizophrenia, and the finding that its expression is decreased in the disorder. We used in situ hybridization histochemistry to measure the relative transcript abundance of calcineurin Agamma and the other catalytic isoforms, Aalpha and Abeta, during development of the Sprague-Dawley rat hippocampus and cerebellum. All three isoforms are present in both regions at all time points [embryonic day 19 (E19) to postnatal day 42 (P42)] and undergo developmental regulation, but differ in their ontogenic profile. Calcineurin Aalpha and Abeta mRNAs increased from E19 through to adulthood, whereas Agamma mRNA was most highly expressed during early developmental stages. Calcineurin Aalpha and Abeta mRNAs positively correlated with synaptophysin mRNA (a synaptic marker), whilst Agamma mRNA was either unrelated to, or negatively correlated, with this transcript. These data confirm that all three calcineurin A subunits are expressed in the rodent brain, and indicate that calcineurin Agamma may have different roles than Aalpha and Abeta. The data also suggest a potential importance of calcineurin Agamma in neurodevelopment, and in the genetically influenced neurodevelopmental disturbance that is thought to underlie schizophrenia.
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PMID:Differential expression of calcineurin A subunit mRNA isoforms during rat hippocampal and cerebellar development. 1636 68

Aspergillus fumigatus is an aggressive opportunistic pathogen of humans as well as a major allergen. Environmental sensing and retrieving essential nutrients from the environment are general metabolic traits associated with the growth of this saprophytic fungus. Two important mediators of calcium signals in eukaryotic cells are the Ca(2+)-binding protein calmodulin and the Ca(2+)/calmodulin-dependent phosphatase calcineurin. Calcineurin is a heterodimer that consists of a catalytic subunit A and a Ca(2+)/calmodulin binding unit. We deleted the A. fumigatus calA gene, which encodes the calcineurin A catalytic subunit, and demonstrated that this gene is not essential in this fungus. The DeltacalA mutant strain has severe defects in growth extension, branching and conidial architecture. Furthermore, the A. fumigatus DeltacalA mutant strain has decreased fitness in a low dose murine infection and cannot grow in fetal bovine serum (FBS). After potassium phosphate was added to liquid FBS, the DeltacalA mutant strain could grow with the characteristic phenotype of the DeltacalA mutation. When A. fumigatus calcineurin is inhibited by tacrolimus in a phosphate depleted medium, there is a reduction in the inorganic phosphate transport and six putative phosphate transporter genes have altered mRNA levels. However, there is no effect on the acid phosphatase activity. These results suggest that calcineurin is involved in the regulation of the PHO pathway in A. fumigatus. Our work on calcineurin opens new venues for the research on sensing and nutrient acquisition in A. fumigatus.
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PMID:Functional characterization of the Aspergillus fumigatus calcineurin. 1699 36

We have been investigating the relationships between genes and behaviors by conducting a systematic and well-defined behavioral test battery with mice that have a mutation on a gene of interest. The behavioral test battery covers a relatively broad range of various behavioral domains such as learning and memory, sensory-motor functions, emotion, motivation, and drug sensitivity/preference. Recently, we subjected mice lacking calcineurin (CN), a calcium/calmodulin protein phosphatase, to the comprehensive behavioral test battery. The mutant mice had a severe working memory deficit, increased locomotor activity, decreased social interaction, and impairments in prepulse and latent inhibition. The abnormalities of CN mutant mice were strikingly similar to those described for schizophrenic patients. Consistent with these findings, human genetics studies in a large sample of affected families detected a significant association of the PPP3CC gene, which encodes the CN gamma catalytic subunit with schizophrenia. The idea that abnormalities in the CN signaling pathway are involved in schizophrenia pathogenesis is consistent with traditional theories of schizophrenia and with many facts known about schizophrenia. A tremendous amount of knowledge about CN has accumulated and, by utilizing this information, the studies on the pathogenesis/pathophysiology of schizophrenia and its related mental disorders will be potentially accelerated. We discuss the potential impact of a large-scale mouse phenotyping project on the study of psychiatric disorders.
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PMID:Investigating gene-to-behavior pathways in psychiatric disorders: the use of a comprehensive behavioral test battery on genetically engineered mice. 1718 13


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