Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ultraviolet (280-nm) irradiation of bovine brain calmodulin results in calcium-dependent changes in its fluorescence emission spectrum. These consist of a decline in the intrinsic tyrosine fluorescence of the protein and the appearance of a new emission maximum at 400 nm. Chromatography of irradiated calmodulin, using Ultrogel AcA 54 and phenyl-agarose columns, yields several distinctive fractions. One of these, representing 2.8% of the total recovered protein and 53% of the total fluorescence emission at 400 nm, was selected for detailed characterization. Analyses performed on acid hydrolysates reveal the presence of dityrosine, a derivative of tyrosine known for its fluorescence near 400 nm, at the level of 0.59-0.89 mol per 16,700 g of protein. Sodium dodecyl sulfate gel electrophoresis experiments demonstrate two components of apparent molecular weights 14,000 (80%) and 16,000 (20%). Observations on the effects of UV irradiation on the thrombic fragments of calmodulin and on related calcium binding proteins (rabbit skeletal muscle troponin C, bovine cardiac troponin C, and parvalbumin) support the interpretation that dityrosine formation in calmodulin results from the intramolecular cross-linking of Tyr-99 and Tyr-138. The dityrosine-containing photoproduct of calmodulin is unable to stimulate the p-nitrophenyl phosphatase activity of calcineurin under standard assay conditions. Fluorescence titrations show a generally weakened interaction with calcium ion occurring in two stages. The pKa of the derivative is considerably higher than that of free dityrosine and is calcium dependent, decreasing from 7.88 to 7.59 on the addition of 3 mM CaCl2. Smooth muscle myosin light chain kinase binds the derivative about 280-fold less effectively than it binds native calmodulin. Of several metal ions tested, only Cd2+ approaches Ca2+ in its ability to promote the appearance of the 400-nm emission band during UV irradiation of calmodulin. Mn2+ and Cu2+ appear to inhibit dityrosine formation. Ascorbic acid, dithiothreitol, and glutathione are also inhibitory.
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PMID:Dityrosine formation in calmodulin. 356 41

A phosphate-acceptor protein was isolated from the skeletal muscle of the Pacific dogfish (Squalus acanthias) displaying properties extremely similar to those of the parvalbumins, i.e., the low-molecular-weight, soluble, Ca-binding muscle proteins found in fish and amphibians. It has the same characteristic UV spectrum, strong affinity for calcium, and immunological crossreactivity with antibodies against homogeneous dogfish parvalbumin. Although it was isolated in three states of aggregation with molecular weights of about 350,000, 75,000, and 25,000, all species dissociate in Na dodecyl sulfate into subunits of 11,000 and 13,000 molecular weight. Furthermore, whereas no phosphorylation of parvalbumins could be demonstrated under any experimental conditions, the aggregated forms could be readily phosphorylated by a cyclic AMP-independent dogfish protein kinase, but not by phosphorylase kinase. One acid-stable and base-labile phosphate group was introduced per subunit which could be rapidly released by a dogfish protein phosphatase, but only very slowly if at all by phosphorylase phosphatase. It is speculated that this "phosphate-acceptor protein" might represent a physiologically active form of the parvalbumins.
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PMID:A phosphate-acceptor protein related to parvalbumins in dogfish skeletal muscle. 436 55

The Ca2+-dependent regulator protein (CDR), also frequently termed "calmodulin" was determined to influence the dephosphorylation of mixed calf thymus histones or purified histones 1, 2A, or 2B by a partially purified bovine brain phosphoprotein phosphatase. CDR increase the rate of dephosphorylation of mixed histones more than 20-fold. With increasing concentrations of mixed histones as substrate, a proportionate increase of CDR concentration was required to maintain maximal expression of histone phosphatase activity. Mixed histones suppressed the activation by CDR of a bovine brain cyclic nucleotide phosphodiesterase activity, with activation being restored by increased quantities of CDR. Dephosphorylation of casein and phosphorylase alpha by the phosphatase preparation was not affected by CDR. These observations support the interpretation that the effects of CDR on histone dephosphorylation are substrate-directed. The rates of dephosphorylation of histones 1, 2A, and 2B by the phosphatase were 4- to 12-fold more rapid at low (sub-micromolar) concentrations of free Ca2+ than at high (200 microM) Ca2+ in incubations containing CDR, but they were unaffected by Ca2+ in incubations without CDR. The addition of stoichiometric quantities of calmodulin increased the apparent Km of the phosphatase for the various histones 2- to 6-fold, while maximal velocities were 4- to 12-fold higher at low than at high added Ca2+. The inhibitory effect of Ca2+ on histone dephosphorylation was immediately reversible by chelation of Ca2+ with EDTA. Ca2+-dependent inhibition of histone 1 or 2B phosphatase activities was also produced by rabbit skeletal muscle troponin C, but not by rabbit skeletal muscle parvalbumin, by poly(L-aspartate) or poly(L-glutamate). The phosphorylated fragment from the NH2-terminal region of either H2A (generated by treatment with N-bromosuccinimide) or H2B (generated by treatment with cyanogen bromide) was dephosphorylated by the phosphatase, with the rates of dephosphorylation being reduced 3- to 6-fold by Ca2+ in incubations containing CDR.
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PMID:Interaction of calmodulin with histones. Alteration of histone dephosphorylation. 625 89

Calmodulin (CaM) and its target enzymes are important regulators of a variety of cellular processes including gene expression and cell cycle progression (Bading, H., Ginty, D. D., and Greenberg, M. E. (1993) Science 260, 181-186; Rasmussen, C. D., and Means, A. R. (1989) EMBO J. 8, 73-82). It has been previously accepted that regulation of CaM-dependent enzyme activity occurs via calcium/calmodulin-dependent activation. We have found that histone H1 is a potent inhibitor of the CaM-dependent activation of mouse calcium/calmodulin-dependent protein kinase II (CaMKII) and of the CaM-dependent protein phosphatase, calcineurin. Inhibition is mediated only by free histone H1; addition of DNA abolishes the inhibitory effect. The effect is not due to a simple interaction of basic (histone) and acidic (CaM) proteins since myelin basic protein and histone H2B, CaMKII substrates more basic than histone H1, did not affect autophosphorylation of CaMKII, and myelin basic protein had no effect on calcineurin activity. The effect is specific to CaM since addition of parvalbumin, a related Ca(2+)-binding protein, did not reverse the effect of histone H1, whereas addition of CaM recovered enzyme activity. These results indicate that free histone H1 levels may specifically affect the ability of CaM to activate its target enzymes and suggests a novel level of control of CaM-dependent enzymes in eukaryotic cells.
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PMID:Activation of calmodulin-dependent enzymes can be selectively inhibited by histone H1. 822 13

A topographical and cellular immunohistochemical analysis was performed on the striatonigral system of rats with unilateral, reversible middle cerebral artery (MCA) occlusion. Antibodies to calcineurin (CaN), parvalbumin (PV), choline acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP) were used in this study. Sixty days after the operation, the ipsilateral striatum showed a characteristic cell type-specific injury in the dorsolateral part of the nucleus (i.e., non-limbic striatum): a marked reduction in the number of medium-sized spinous neurons expressing CaN immunoreactivity and a selective sparing of PV- and ChAT-positive interneurons. There was also a marked depletion of striatonigral afferents visualized by CaN immunostaining in the lateral portion of the substantia nigra pars reticulata, which is considered to be implicated with motor function. In addition, it was noted that such striatonigral involvement was accompanied by marked gliosis showing strong GFAP immunolabeling. The present data suggest that rats with reversible MCA occlusion can be a useful animal model for studying cell type-specific ischemic injury and subdivisional involvement of the striatonigral pathway as a part of the cortico-subcortical loop subserving motor function.
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PMID:Striatonigral involvement following transient focal cerebral ischemia in the rats: an immunohistochemical study on a reversible ischemia model. 838 49

We aimed to clarify the topology and immunohistochemistry of CO2/H+-sensitive neurons in the ventral medullary surface (VMS), the central chemoreceptor area in rats. Inhalation of 3 and 7% CO2 in air significantly decreased pH in arterial blood and increased paCO2, which caused hyperpneic and tachypneic responses. Following inhalation of 3 and 7% CO2 in air for 5 min, the density of c-Fos-immunoreactive (IR) neurons increased stepwise not only in the 3rd-5th divisions of the VMS (between the caudal end of the nucleus corporis trapezoidei and the caudal end of the area postrema), but also in the rostroventromedial medulla (RVMM). Following inhalation of 7% CO2 in air for 5 min, glutamate-, glutamic acid decarboxylase (GAD)-, calcineurin- and cAMP-IR neurons were found not only in the VMS, but also in the RVMM. The topology of these neurons was similar to that of the c-Fos-IR neurons. No immunoreactivity was found for serotonin, substance P, somatostatin, cholecystokinin-octapeptide, methionine-enkephalin, choline acetyltransferase, tyrosine hydroxylase, phenylethanolamine N-methyltransferase, NO-synthase, S-100, calbindin-D, calmodulin, or parvalbumin. The densities of c-Fos-, glutamate-, GAD-, calcineurin- and cAMP-IR neurons were almost zero in the 1st division of the VMS, but became higher along the 2nd-4th divisions of the VMS. Regression lines of the density against the 1st-4th divisions of the VMS were significantly linear. These results indicate that H+-sensitive neurons are common in the 4th-5th divisions of the VMS, and that they are glutamatergic, GABAergic, and containing calcineurin and cAMP.
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PMID:Topology and immunohistochemistry of proton-sensitive neurons in the ventral medullary surface of rats. 947 76

Mammalian skeletal muscle shows an enormous variability in its functional features such as rate of force production, resistance to fatigue, and energy metabolism, with a wide spectrum from slow aerobic to fast anaerobic physiology. In addition, skeletal muscle exhibits high plasticity that is based on the potential of the muscle fibers to undergo changes of their cytoarchitecture and composition of specific muscle protein isoforms. Adaptive changes of the muscle fibers occur in response to a variety of stimuli such as, e.g., growth and differentition factors, hormones, nerve signals, or exercise. Additionally, the muscle fibers are arranged in compartments that often function as largely independent muscular subunits. All muscle fibers use Ca(2+) as their main regulatory and signaling molecule. Therefore, contractile properties of muscle fibers are dependent on the variable expression of proteins involved in Ca(2+) signaling and handling. Molecular diversity of the main proteins in the Ca(2+) signaling apparatus (the calcium cycle) largely determines the contraction and relaxation properties of a muscle fiber. The Ca(2+) signaling apparatus includes 1) the ryanodine receptor that is the sarcoplasmic reticulum Ca(2+) release channel, 2) the troponin protein complex that mediates the Ca(2+) effect to the myofibrillar structures leading to contraction, 3) the Ca(2+) pump responsible for Ca(2+) reuptake into the sarcoplasmic reticulum, and 4) calsequestrin, the Ca(2+) storage protein in the sarcoplasmic reticulum. In addition, a multitude of Ca(2+)-binding proteins is present in muscle tissue including parvalbumin, calmodulin, S100 proteins, annexins, sorcin, myosin light chains, beta-actinin, calcineurin, and calpain. These Ca(2+)-binding proteins may either exert an important role in Ca(2+)-triggered muscle contraction under certain conditions or modulate other muscle activities such as protein metabolism, differentiation, and growth. Recently, several Ca(2+) signaling and handling molecules have been shown to be altered in muscle diseases. Functional alterations of Ca(2+) handling seem to be responsible for the pathophysiological conditions seen in dystrophinopathies, Brody's disease, and malignant hyperthermia. These also underline the importance of the affected molecules for correct muscle performance.
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PMID:Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease. 1089 34

To elucidate the molecular basis of muscle atrophy, we have performed the serial analysis of gene expression (SAGE) method with control and immobilized muscles of 10 rats. The genes that expressed >0.5% in muscle are involved in the following three functions: 1) contraction (troponin I, C and T; myosin light chain 1-3; actin; tropomyosin; and parvalbumin), 2) energy metabolism (cytochrome c oxidase I and III, creatine kinase, glyceraldehyde-3-phosphate-dehydrogenase, phosphoglycerate mutase, ATPase 6, and aldolase A), and 3) housekeeping (lens epithelial protein). Muscle atrophy appears to be caused by changes in mRNA levels of specific regulators of proteolysis, protein synthesis, and contractile apparatus assembling, such as polyubiquitin, elongation factor 2, and nebulin. Immobilization has produced a decrease more than threefold in gene expression of enzymes involved in energy metabolism, especially ATPase, cytochrome c oxidase, NADH dehydrogenase, and protein phosphatase 1. Differential gene expressions of selenoprotein W and uroporphyrinogen decarboxylase, which can be involved in oxidative stress, were also observed. Other genes with various functions, such as cholesterol metabolism and growth factors, were also differentially expressed. Moreover, novel genes regulated by immobilization were discovered. Thus, the current study allows a better understanding of global muscle characteristics and the molecular mechanisms of sedentarity and sarcopenia.
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PMID:Characterization of control and immobilized skeletal muscle: an overview from genetic engineering. 1125 86

C(60)-Fullerene trisamine adducts inhibit neuronal nitric oxide synthase and calcineurin phosphatase activities in a manner completely reversible by calmodulin. As measured by difference spectroscopy, D(3)-trisamine and C(3)-semiamine fullerene adducts displace trifluoperazine bound to calmodulin coincident with their binding. These binding events are complete at a molar ratio of 4 mol added fullerene per mole calmodulin. Trisamine fullerene adducts alter the native electrophoretic mobility of calmodulin, producing a heterogeneity of bands with associated fullerene. D(3)- and C(3)-trisamine fullerene adducts interact with dansylated calmodulin, producing a 50% loss of maximal fluorescence at concentrations of 30 nM. At higher concentrations than those required to inhibit neuronal nitric oxide synthase, trisamine fullerene adducts inhibit nitric oxide formation by the cytokine-inducible nitric oxide synthase isoform. These inhibitions are fully reversible by calmodulin and skeletal muscle troponin C but not by skeletal muscle parvalbumin. Of the trisamine fullerene adducts tested only the C(3)- and D(3)-semiamine adducts inhibit Ca(2+)-dependent nitric oxide production in GH(3) pituitary cells. These observations support the proposal that trisamine C(60)-fullerene adducts are potent calmodulin antagonists, some of which display activity in intact cellular systems.
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PMID:Trisamine C(60)-fullerene adducts inhibit neuronal nitric oxide synthase by acting as highly potent calmodulin antagonists. 1188 98

The purpose of this study was to determine whether induced expression of the Ca2+ buffering protein parvalbumin (PV) in slow-twitch fibres would lead to alterations in physiological, biochemical and molecular properties reflective of a fast fibre phenotype. Transgenic (TG) mice were generated that overexpressed PV in slow (type I) muscle fibres. In soleus muscle (SOL; 58 % type I fibres) total PV expression was 2- to 6-fold higher in TG compared to wild-type (WT) mice. Maximum twitch and tetanic tensions were similar in WT and TG but force at subtetanic frequencies (30 and 50 Hz) was reduced in TG SOL. Twitch time-to-peak tension and half-relaxation time were significantly decreased in TG SOL (time-to-peak tension: 39.3 +/- 2.6 vs. 55.1 +/- 4.7 ms; half-relaxation time: 42.1 +/- 3.5 vs. 68.1 +/- 9.6 ms, P < 0.05 for TG vs. WT, respectively; n = 8-10). There was a significant increase in expression of type IIa myosin heavy chain (MHC) and ryanodine receptor at the mRNA level in TG SOL but there were no differences in MHC expression at the protein level and thus no difference in fibre type. Whole muscle succinate dehydrogenase activity was reduced by 12 +/- 0.4 % in TG SOL and single fibre glycerol-3-phosphate dehydrogenase activity was decreased in a subset of type IIa fibres. These differences were associated with a 64 % reduction in calcineurin activity in TG SOL. These data show that overexpression of PV, resulting in decreased calcineurin activity, can alter the functional and metabolic profile of muscle and influence the expression of key marker genes in a predominantly slow-twitch muscle with minimal effects on the expression of muscle contractile proteins.
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PMID:Alterations in slow-twitch muscle phenotype in transgenic mice overexpressing the Ca2+ buffering protein parvalbumin. 1256 45


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