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 unique isoform of the catalytic subunit of calmodulin-dependent protein phosphatase (CaM-PrP) was cloned from a murine testis library. The cDNA sequence of 1964 base pairs contained an open reading frame encoding a protein of 513 amino acids (Mr approximately 58,706), the predicted isoelectric point of which (pI 7.1) was much more basic than those of brain isoforms (pI 5.6-5.8). The deduced amino acid sequence was 77-81% identical to two other murine CaM-PrP genes and displayed a distinct Southern blot hybridization pattern, indicating that it was derived from a separate gene (type 3). High amounts of a 2800-nucleotide mRNA transcript were observed in testis, whereas mRNA species were not detectable in brain; thus, it seems likely that this CaM-PrP represents a nonneural isoenzyme. Measurements of CaM-PrP mRNA during testicular development showed a dramatic increase in expression during weeks 4-6, correlating with the later stages of spermatogenesis. These data suggest that this phosphatase isoform may be involved in germ-cell function and are consistent with the report of a flagellum-associated form of CaM-PrP that may regulate sperm motility [Tash, J. S., Krinks, M., Patel, J., Means, R. L., Klee, C. B. & Means, A. R. (1988) J. Cell Biol. 106, 1625-1633].
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PMID:Molecular cloning of a calmodulin-dependent phosphatase from murine testis: identification of a developmentally expressed nonneural isoenzyme. 130 45

Biochemical properties of neuronal protein phosphatases from Aplysia californica were characterized. Dephosphorylation of phosphorylase alpha by extracts of abdominal ganglia and clusters of sensory neurons from pleural ganglia was demonstrated. Type-1 protein phosphatase (PrP-1) was identified in these extracts by the dephosphorylation of the beta-subunit of phosphorylase kinase and its inhibition by the protein, inhibitor-2. Type-2A protein phosphatase (PrP-2A) was demonstrated by the dephosphorylation of the alpha-subunit of phosphorylase kinase, which was insensitive to inhibitor-2. As in vertebrate tissues, only four enzymes, PrP-1 (47%), PrP-2A (42%), PrP-2B (11%), and PrP-2C (less than 1%), accounted for all the cellular protein phosphatase activity dephosphorylating phosphorylase kinase. Aplysia PrP-1 and PrP-2A were potently inhibited by okadaic acid, with PrP-1 being approximately 20-fold more sensitive than PrP-2A. By comparison, purified PrP-2A from rabbit skeletal muscle was 15- to 20-fold more sensitive to okadaic acid than PrP-1 from the same source. Only PrP-1 was associated with the particulate fractions from Aplysia neurons, whereas PrP-1 and PrP-2A, -2B, and -2C were all present in the cytosol. Extraction of the particulate PrP-1 decreased its sensitivity to okadaic acid by sixfold, suggesting that cellular factor(s) affect its sensitivity to this inhibitor. In most respects, protein phosphatases from Aplysia neurons resemble their mammalian counterparts, and their biochemical characterization sets the stage for examining the role of these enzymes in neuronal plasticity, and in learning and memory.
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PMID:Characterization of neuronal protein phosphatases in Aplysia californica. 131 Jul 28

A cDNA for an alternatively spliced variant of the testis-specific catalytic subunit of calmodulin dependent protein phosphatase (CaM-PrP) was cloned from a human testis library. The nucleotide sequence of 2134 base pairs (bp) encodes a protein of 502 amino acids (Mr approximately 57,132) and pI 7.0. The cDNA sequence differs from the murine form of this gene by a 30 bp deletion in the coding region, the position of which matches those in the two other genes for the catalytic subunit. These data indicate that this alternative splicing event arose prior to the divergence of the three genes. The deduced sequence of the human protein is only 88% identical to the homologous murine form, in striking contrast to the other two CaM-PrP catalytic subunits which are highly conserved between mouse and human (approximately 99%); this indicates a more rapid rate of evolution for the testis-specific gene. Analysis of Southern blots containing DNA from human-hamster somatic cell hybrids show that the gene is on human chromosome 8.
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PMID:Molecular cloning and chromosomal mapping of the human gene for the testis-specific catalytic subunit of calmodulin-dependent protein phosphatase (calcineurin A). 133 77

Polyclonal antibodies to the catalytic subunit of protein phosphatase 2A (PrP-2A) from bovine brain were prepared by immunizing rabbits and then purified by antigen-affinity column chromatography. The purified antibodies recognized only PrP-2A among proteins examined, including calcineurin and PrP-1. The antibodies cross-reacted only with a protein in the crude homogenate from rat brain, which comigrated with the catalytic subunit of PrP-2A on SDS-PAGE. The antibodies completely inhibited the activity of PrP-2A, and immunoprecipitated the purified enzyme. Immunoblot analysis demonstrates that, among the subcellular fractions from rat brain, the cytosol fraction and the synaptosomal cytosol fraction show high immunoreactivities, and that any of examined regions of rat brain shows immunoreactivity more or less, in which the caudatoputamen was highest. Immunohistochemical studies demonstrate that the enzyme is distributed widely in various regions of rat brain and that the immunoreactivity is localized mainly in neurons. In general, immunostaining of neurons was strong in neurites as well as somata. It was noted that intracerebellar nuclei were strongly stained in both neuronal somata and dendrites. Amygdaloid complex, thalamus, neocortex, hippocampal formation, and caudatoputamen were moderately stained.
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PMID:Characterization of polyclonal antibodies to brain protein phosphatase 2A and immunohistochemical localization of the enzyme in rat brain. 254 11

A calcium/calmodulin-dependent protein kinase termed CaM-kinase II is a major component of synaptic junctions from forebrain and constitutes approximately 12% of total synaptic junction protein. CaM-kinase II phosphorylates at least seven polypeptides that are enriched in synaptic junctions, of which two represent the 50- and 60-kilodalton subunits of the protein kinase. In this report the nature of endogenous protein phosphatases which dephosphorylate each of the seven synaptic junction phosphoproteins was examined. Assays of synaptic junctions and other subcellular fractions from rat forebrain for type-1 and type-2 protein phosphatases revealed that protein phosphatase 1 (PrP-1) was specifically enriched in synaptic junctions with respect to cytosolic fractions. The activity of type-2 protein phosphatases was very low in synaptic junctions. Homogeneous PrP-1 from rabbit skeletal muscle was found to dephosphorylate each of the seven phosphoproteins in synaptic junctions. Inhibitors-1 and -2 were found to inhibit endogenous protein phosphatase activity by 70 to 80%. Since inhibitors-1 and -2 are specific inhibitors of PrP-1, these results indicate that this enzyme accounts for the majority of endogenous protein phosphatase activity in synaptic junctions. Approximately 15% of the protein phosphatase activity in synaptic junctions was type 2A, whereas PrP-2B and PrP-2C accounted for little, if any, of the activity toward endogenous or exogenous phosphoproteins. These results indicate that PrP-1 may be important in controlling the state of phosphorylation of synaptic junction proteins.
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PMID:Identification of protein phosphatase 1 in synaptic junctions: dephosphorylation of endogenous calmodulin-dependent kinase II and synapse-enriched phosphoproteins. 300 Dec 44

Two broad-specifically protein phosphatases, termed protein phosphatase-1 (PrP-1) and protein phosphatase-2A (PrP-2A), accounting for all the hepatic activity regulating glycogen phosphorylase, were measured in spontaneously diabetic Chinese hamsters exhibiting persistent glycosuria. When compared with genetically related inbred sublines free of glycosuria, diabetic animals demonstrated approximately 25% increase in PrP-1 activity measured either in crude tissue extracts or in cytosols fractionated by ion-exchange chromatography. No significant alteration in total PrP-2A activity was observed in the diabetic animals. These findings indicate that a specific change in hepatic PrP-1 is associated with genetically acquired diabetes in Chinese hamsters. In contrast to reported data using animals with experimentally induced diabetes mellitus, hepatic PrP-1 was increased in the spontaneously diabetic Chinese hamsters. The data suggests that distinct alterations in PrP-1 and associated metabolic consequences are exhibited by different types of diabetes.
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PMID:Increase in liver protein phosphatase-1 in spontaneously diabetic Chinese hamsters. 303 94

Choline acetyltransferase (ChAT) and choline transport are decreased after nitrosative stress. ChAT activity is altered in scrapie-infected neurons, where oxidative stress develops. Cellular prion protein (PrPc) may play a neuroprotective function in participating in the redox control of neuronal environment and regulation of copper metabolism, a role impaired when PrPc is transformed into PrPSc in prion pathologies. The complex cross-talk between PrPc and cholinergic neurons was analyzed in vitro using peroxynitrite and Cu2+ treatments on nerve endings isolated from Torpedo marmorata, a model of the motoneuron pre-synaptic element. Specific interactions between solubilized synaptic components and recombinant ovine prion protein (PrPrec) could be demonstrated by Biacore technology. Peroxynitrite abolished this interaction in a concentration-dependent way and induced significant alterations of neuronal targets. Interaction was restored by prior addition of peroxynitrite trapping agents. Cu2+ (in the form of CuSO4) treatment of synaptosomes triggered a milder oxidative effect leading to a bell-shaped increase of PrPrec binding to synaptosomal components, counteracted by the natural thiol agents, glutathione and thioredoxin. Copper(II)-induced modifications of thiols in several neuronal proteins. A positive correlation was observed between PrPrec binding and immunoreactive changes for calcineurin B and its partners, suggesting a synergy between calcineurin complex and PrP for copper regulation.
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PMID:Selective prion protein binding to synaptic components is modulated by oxidative and nitrosative changes induced by copper(II) and peroxynitrite in cholinergic synaptosomes, unveiling a role for calcineurin B and thioredoxin. 1471 1

A method is described to measure threonine phosphorylation of the Na-K-2Cl cotransporter in ferret erythrocytes using readily available antibodies. We show that most, if not all, cotransporter in these cells is NKCC1, and this was immunoprecipitated with T4. Cotransport rate, measured as 86Rb influx, correlates well with threonine phosphorylation of T4-immunoprecipitated protein. The cotransporter effects large fluxes and is significantly phosphorylated in cells under control conditions. Transport and phosphorylation increase 2.5- to 3-fold when cells are treated with calyculin A or Na+ arsenite. Both fall to 60% control when cell [Mg2+] is reduced below micromolar or when cells are treated with the kinase inhibitors, 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine or staurosporine. Importantly, these latter interventions do not abolish either phosphorylation or transport suggesting that a phosphorylated form of the cotransporter is responsible for residual fluxes. Our experiments suggest protein phosphatase 1 (PrP-1) is extremely active in these cells and dephosphorylates key regulatory threonine residues on the cotransporter. Examination of the effects of kinase inhibition after cells have been treated with high concentrations of calyculin indicates that residual PrP-1 activity is capable of rapidly dephosphorylating the cotransporter. Experiments on cotransporter precipitation with microcystin sepharose suggest that PrP-1 binds to a phosphorylated form of the cotransporter.
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PMID:Regulation of erythrocyte Na-K-2Cl cotransport by threonine phosphorylation. 1599 36

Amyloid-beta protein (A beta) and the scrapie isoform of prion protein (PrPSs) have a central role in the pathogenesis of Alzheimer's disease (AD) and prion-related encephalopathies (PRE), respectively. In both disorders, the deposition of these misfolded proteins is accompanied by apoptotic neuronal loss. However, the pathogenesis and molecular basis of A beta- and PrPSc-neurotoxic effects are not completely understood. The Ca2+/calmodulin-dependent phosphatase calcineurin (CaN), through the dephosphorylation of the proapoptotic protein BAD, may be the link between Ca2+homeostasis deregulation and apoptotic neuronal death. In this study we used primary cultures of rat brain cortical neurons in order to investigate whether A beta and PrP affect CaN activity. We observed that synthetic peptides of A beta (A beta 25-35 and A beta 1-40) and PrP (PrP106-126) increased CaN activity, but did not affect the levels of this protein phosphatase. Moreover, we found that these peptides reduced the levels of BAD phosphorylated at serine residue 112, and this effect was prevented by the CaN inhibitor FK506. Since dephosphorylated BAD translocates to mitochondria, where it triggers cytochrome c release, we determined the levels of BAD in mitochondrial and cytosolic fractions. The data obtained showed that A beta- and PrP-treated neurons had higher levels of BAD in mitochondria than control neurons. This increase in mitochondrial BAD levels was matched by a decrease in cytochrome c. FK506 prevented the alterations of mitochondrial BAD and cytochrome c levels induced by A beta and PrP peptides. Taken together the data suggest that A beta and PrP increased CaN activity, inducing BAD dephosphorylation and translocation to mitochondria and, subsequently, cytochrome c release that may trigger an apoptotic cascade. Therefore, therapeutic strategies targeting CaN might be valuable for these neurodegenerative disorders.
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PMID:Overactivation of calcineurin induced by amyloid-beta and prion proteins. 1829 34

Prion diseases are fatal neurodegenerative disorders for which there is no effective treatment. Because the cellular prion protein (PrP(C)) is required for propagation of the infectious scrapie form of the protein, one therapeutic strategy is to reduce PrP(C) expression. Recently FK506, an inhibitor of the FKBP family of peptidyl prolyl isomerases, was shown to increase survival in animal models of prion disease, with proposed mechanisms including calcineurin inhibition, induction of autophagy, and reduced PrP(C) expression. We show that FK506 treatment results in a profound reduction in PrP(C) expression due to a defect in the translocation of PrP(C) into the endoplasmic reticulum with subsequent degradation by the proteasome. These phenotypes could be bypassed by replacing the PrP(C) signal sequence with that of prolactin or osteopontin. In mouse cells, depletion of ER luminal FKBP10 was almost as potent as FK506 in attenuating expression of PrP(C). However, this occurred at a later stage, after translocation of PrP(C) into the ER. Both FK506 treatment and FKBP10 depletion were effective in reducing PrP(Sc) propagation in cell models. These findings show the involvement of FKBP proteins at different stages of PrP(C) biogenesis and identify FKBP10 as a potential therapeutic target for the treatment of prion diseases.
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PMID:Inhibition of the FKBP family of peptidyl prolyl isomerases induces abortive translocation and degradation of the cellular prion protein. 2676 98


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