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

---

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

The inhibitory protein that binds calmodulin and thus prevents activation of several Ca2+-dependent enzymes by calmodulin is shown to also bind four Ca2+ per mol of protein with high affinity (Kd less than or equal to 10(-6) M). On the basis of its Ca2+- binding properties and its localization to nervous tissue, the inhibitory protein is now called "calcineurin." Calcineurin is composed of two subunits: calcineurin A (61,000 Mr) which interacts with calmodulin in a Ca2+-dependent fashion, and calcineurin B (15,000 Mr) which binds Ca2+. The interaction of calcineurin A with calcineurin B is independent of Ca2+ or Mg2+. The dual interaction of calcineurin A with two different Ca2+-binding components and the high affinity of calcineurin for Ca2+ suggest a possible role for calcineurin in the regulation of free Ca2+ concentrations in the nervous system. Calcineurin may thereby modulate the release and action of neurotransmitters.
...
PMID:Calcineurin: a calcium- and calmodulin-binding protein of the nervous system. 29 20

The structurally unrelated immunosuppressants FK506 and cyclosporin A (CsA) act similarly, inhibiting a Ca(2+)-dependent signal required for interleukin-2 transcription and T-cell activation. Each drug binds to its cytosolic receptor, FKBP-12 and cyclophilin, respectively, and the drug-receptor complexes inhibit the Ca2+/calmodulin-dependent protein phosphatase, calcineurin. In yeast, calcineurin has been implicated in recovery from alpha-mating factor arrest. Here we show that FK506 bound to yeast FKBP-12 appears to form a complex with yeast calcineurin. Moreover, recovery from mating factor arrest is highly sensitive to FK506 or CsA, and this sensitivity requires the presence of FKBP-12 or cyclophilin, respectively. These results define a key physiological target of an FK506- and CsA-sensitive signal pathway in yeast, suggest a high degree of mechanistic conservation with mammalian cells, and indicate that further examination of the yeast system should provide insight into the same process in T cells.
...
PMID:Calcineurin mediates inhibition by FK506 and cyclosporin of recovery from alpha-factor arrest in yeast. 128 18

The immunosuppressants cyclosporine and FK506 (tacrolimus) are extremely potent inhibitors of T-lymphocyte activation. Recent studies have shown that these agents are actually prodrugs that become active only when bound to specific members of the cyclophilin or FK506 binding protein receptor gene families. The cyclosporine-cyclophilin or FK506-FK506 binding protein receptor complexes interact with a key component of the T-cell antigen receptor signal transduction pathway, the calcium-calmodulin-dependent phosphoprotein phosphatase calcineurin. The drug-receptor complexes inhibit the phosphatase activity of calcineurin and thereby prevent transcriptional activation of the interleukin-2 gene.
...
PMID:Recent advances in the mechanism of action of cyclosporine and FK506. 128 80

Two isoforms of calcineurin beta subunit(beta 1 and beta 2) were identified in rat testis by a monoclonal antibody Va1. Both beta 1 and beta 2 were recovered in calmodulin binding protein fraction and showed calcium shift on SDS-polyacrylamide gel electrophoresis which is the specific character for EF-hand calcium binding protein. beta 2 showed same apparent molecular weight on SDS-PAGE as that of brain calcineurin beta and was found in wide variety of tissues. beta 1 was shown to have six amino acid polypepeptide sequence and it showed higher molecular weight than brain beta and was specific for testis.
...
PMID:Identification of testis specific calcineurin beta subunit isoform by a monoclonal antibody and detection of a specific six amino acid sequence. 131 15

Specific polyclonal antibodies that distinguish the two distinct isoforms of the catalytic subunit of calmodulin-dependent protein phosphatase, calcineurin A alpha and A beta, were prepared, and the distribution of calcineurin A alpha and A beta in rat brain was studied using immunochemical and immunocytochemical techniques. Immunochemical measurement revealed that the regional distributions of the two isoforms differed and that A alpha was more abundant than A beta in the rat brain. The subcellular distribution patterns of both isoforms were similar. Both isoforms were highly enriched in cytosolic fractions, including the synaptosomal cytosol. Immunocytochemical analysis revealed that both A alpha and A beta immunoreactivities differed in regional and cellular localizations. These different patterns of expression suggest that the two isoforms of calcineurin A may each have specific functions in modulating neuronal activity in particular cell types.
...
PMID:Distinct cellular expression of calcineurin A alpha and A beta in rat brain. 131 51

We have investigated regional and temporal alterations in Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) and calcineurin (Ca2+/calmodulin-dependent protein phosphatase) after transient forebrain ischemia. Immunoreactivity and enzyme activity of CaM kinase II decreased in regions CA1 and CA3, and in the dentate gyrus, of the hippocampus early (6-12 h) after ischemia, but the decrease in immunoreactivity gradually recovered over time, except in the CA1 region. Furthermore, the increase in Ca2+/calmodulin-independent activity was detected up to 3 days after ischemia in all regions tested, suggesting that the concentration of intracellular Ca2+ increased. In contrast to CaM kinase II, as immunohistochemistry and regional immunoblot analysis revealed, calcineurin was preserved in the CA1 region until 1.5 days and then lost with the increase in morphological degeneration of neurons. Immunoblot analysis confirmed the findings of the immunohistochemistry. These results suggest that there is a difference between CaM kinase II and calcineurin in regional and temporal loss after ischemia and that imbalance of Ca2+/calmodulin-dependent protein phosphorylation-dephosphorylation may occur.
...
PMID:Regional and temporal alterations in Ca2+/calmodulin-dependent protein kinase II and calcineurin in the hippocampus of rat brain after transient forebrain ischemia. 131 54

The Ca(2+)- and calmodulin-dependent protein phosphatase calcineurin is inhibited by the immunosuppressant drug cyclosporin A in the presence of cyclophilin A or B. Of the two isoforms, cyclophilin B is more potent by a factor of 2-5 when either the phosphoprotein [32P]casein or the [32P]phosphoserine [Ser(32P)] form of the 19-residue bovine cardiac cAMP-dependent protein kinase regulatory subunit peptide RII, [Ser(32P)15]RII, is used as substrate. With [Ser(32P15]RII as substrate, the concentrations of the cyclosporin A.cyclophilin A and cyclosporin A.cyclophilin B complexes, which cause 50% inhibition of calcineurin activity, are 120 and 50 nM, respectively. Lowering the concentration of calcineurin 80% with [32P]casein as substrate lowered the apparent inhibition constant for each complex even further; 50% inhibition of calcineurin was observed at 40 nM for cyclosporin A.cyclophilin A, whereas it was less than 10 nM for cyclosporin A.cyclophilin B. In all inhibition assays with [32P]casein or [Ser(32P)15]RII, the concentration of calcineurin required for measurable phosphatase activity is such that these complexes behave as tight-binding inhibitors of calcineurin, and steady-state kinetics cannot be used to assess inhibition patterns or Ki values. Limited trypsinization of calcineurin produces a fragment that is still inhibited, indicating that the interaction of cyclosporin.cyclophilin with calcineurin does not require either calmodulin or Ca2+.
...
PMID:Cyclosporin-mediated inhibition of bovine calcineurin by cyclophilins A and B. 131 36

The inhibitory action of synthetic pyrethroids and some chlorinated hydrocarbon insecticides on the neural calcium-calmodulin-dependent protein phosphatase, calcineurin, was studied using one radiotracer and two colorimetric methods. It was found that all insecticidal Type II pyrethroids (cypermethrin, deltamethrin and fenvalerate) are potent inhibitors of isolated calcineurin from bovine brain. Their IC50 values were approximately 10(-9) to 10(-11) M. By contrast, neither noninsecticidal chiral isomers of these pyrethroids, neuroactive Type I pyrethroids nor neuroactive chlorinated hydrocarbon insecticides showed comparable potencies against this enzyme. To confirm the action of Type II pyrethroid in situ, isolated intact rat brain synaptosomes were incubated with [32P]phosphoric acid and subsequently depolarized in the presence and absence of 0.1 microM deltamethrin. As expected, there was a sharp rise in protein phosphorylation due to the action of calcineurin. Deltamethrin caused a distinct delay in the dephosphorylation process. The results clearly indicate that calcineurin is specifically inhibited by Type II pyrethroids.
...
PMID:Specific inhibition of calcineurin by type II synthetic pyrethroid insecticides. 131 45

In the mammalian brain, there are multiple catalytic subunits for the Ca(2+)- and calmodulin-dependent protein phosphatase [also called protein phosphatase 2B (PP-2B) and calcineurin] that are derived from two structural genes. The coding sequences of these two genes are distinguished by the absence (PP2B alpha 1) or the presence (PP2B alpha 2) of an amino terminus containing polyproline. Both of these genes can produce intragenic isoforms through alternative splicing. In the present study, a potential phylogenetic relationship of these genes was inferred from analysis of genomic DNA and from studies of mRNA and protein expression. Southern blot analysis showed unique restriction fragments for both genes in seven mammalian species; however, in organisms from two nonmammalian vertebrates (chicken and lizard), hybridization was observed only for PP2B alpha 1. In agreement with these results, Northern blots of mammalian brain RNA showed transcripts for both genes, with about two to three times more of the PP2B alpha 1 mRNAs, whereas in chicken and lizard, only PP2B alpha 1 transcripts were detected. An analysis of protein expression by two-dimensional electrophoresis was also consistent with these findings. For the purified mammalian brain protein, eight to ten variants were observed with isoelectric points of 5.2-5.8; immunoblot analysis using anti-peptide antibodies indicated that the majority of these were PP2B alpha 1 forms. In chicken brain, multiple isoforms were recognized by antibodies against the PP2B alpha 1 forms, but no reactivity was seen with those against the PP2B alpha 2 forms. Taken together, these findings suggest that: (i) in mammals, the predominant catalytic subunit isoforms in brain are PP2B alpha 1 products and (ii) the gene for the polyproline-containing catalytic subunit of calmodulin-dependent phosphatase (PP2B alpha 2) may have evolved after the avian/reptilian branching point, perhaps to carry out a role(s) of particular significance in mammals.
...
PMID:Molecular and phylogenetic analysis of calmodulin-dependent protein phosphatase (calcineurin) catalytic subunit genes. 131 21

Type 2C protein phosphatase (PP2C) is one of four major serine-threonine specific phosphoprotein phosphatases which modulate various intracellular activities. By in situ hybridization analysis of the adult rat, expression signals of mRNA for PP2C were observed most highly in the granule cells and Purkinje cells of the cerebellum, the pyramidal cells of the hippocampus and granule cells of the dentate gyrus, and plexus choroideus of the lateral ventricle, whereas moderate levels of its expression were observed in the medial habenula, piriform cortex and the pineal body. Several discrete nuclei of the brainstem including pars compacta of the substantia nigra, the pontine nuclei, and the locus ceruleus expressed the mRNA moderately. Weak expression of PP2C mRNA was observed in mitral and internal granule cells of the olfactory bulb, spinal cord gray matter, the cerebral neocortex, thalamic and hypothalamic nuclei. Only faint expression was detected in the caudate putamen. These patterns of expression are different from that of calcineurin/PP2B reported by other immunohistochemical studies and it is suggested that various neuronal proteins are differentially dephosphorylated by the different types of PP.
...
PMID:Localization of mRNA for protein phosphatase 2C in the brain of adult rats. 132 Jul 18


1 2 3 4 5 6 7 8 9 10 Next >>

---