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)

When the stimuli by nerve impulses, neurotransmitters, hormones, peptides and growth factors are administered to the neurons, one of the responses of the nerve cells is the enhancement of Ca2+ influx and/or the release of Ca2+ from the intracellular storage site. Ca2+ may be related to several types of neuronal functions such as biosynthesis of neurotransmitters, stimulus-secretion coupling of neurotransmitters and hormones, microtubule assembly-disassembly cycle and many metabolic reactions. Although the precise molecular mechanism mediating the actions of Ca2+ in the brain remains to be elucidated, accumulating evidence suggests that the actions of Ca2+ are mediated through Ca2(+)-binding proteins. The role of troponin C, a Ca2(+)-binding protein, was extensively studied in the skeletal muscle first. Subsequently calmodulin, a ubiquitous Ca2(+)-binding protein, was found to be widely distributed in many tissues and to be involved in a variety of Ca2(+)-mediated cellular processes. In an attempt to elucidate Ca2+ actions in the central nervous system, we have been studying Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) and calcineurin (Ca2+/calmodulin-dependent protein phosphatase). These enzymes have many common substrates and, therefore, may be involved in the neuronal functions via phosphorylation and dephosphorylation of specific proteins.
...
PMID:[A study on the role and mechanism of intracellular Ca2+ in the central nervous system]. 217 89

The calcium-dependent binding of melittin by calmodulin effectively inhibits the hemolytic activity of melittin in suspensions of washed rabbit erythrocytes. Protection is also obtained with troponin C (+/-Ca++), denatured phosphorylase kinase, and denatured calcineurin but not with whole troponin or the native enzymes. These effects can be used both in assays for melittin in venom samples and in determinations of calmodulin or related proteins.
...
PMID:Effects of calmodulin and related proteins on the hemolytic activity of melittin. 299 62

An anti-calmodulin monoclonal antibody having an absolute requirement for Ca2+ has been produced from mice immunized with a mixture of calmodulin and calmodulin-binding proteins. Radioimmune assays were developed for the determination of its specificity. the epitope for this antibody resides on the COOH-terminal half of the mammalian protein. Plant calmodulin or troponin C had little reactivity. The apparent affinity of the antibody for calmodulin was increased approximately 60-fold in the presence of heart calmodulin-dependent phosphodiesterase. The presence of heart phosphodiesterase in the radioimmune assay greatly enhanced the sensitivity for calmodulin. The intrinsic calmodulin subunit of phosphorylase kinase and calmodulin which was bound to brain phosphodiesterases was also recognized with high affinity by the antibody. The antibody reacted poorly with calmodulin which was bound to heart or brain calcineurin, skeletal muscle myosin light chain kinase, or other calmodulin-binding proteins. In direct binding experiments, most of the calmodulin-binding proteins studied were unreactive with the antibody. This selectivity allowed purification of heart and two brain calmodulin-dependent cyclic nucleotide phosphodiesterase isozymes on immobilized antibody affinity columns. Phosphodiesterase activity was adsorbed directly from crude samples and specifically eluted with EGTA. Isozyme separation was accomplished using a previously described anti-heart phosphodiesterase monoclonal antibody affinity support. The brain isozymes differed not only in reactivity with the anti-phosphodiesterase antibody, but also in apparent subunit molecular weight, and relative specificity for cAMP and cGMP as substrates. The calmodulin activation constants for the brain enzymes were 10-20-fold greater than for the heart enzyme. The data suggest that the binding of ligands to Ca2+/calmodulin induce conformation changes in calmodulin which alter reactivity with the anti-calmodulin monoclonal antibody. The differential antibody reactivity toward calmodulin-enzyme complexes indicates that target proteins either induce very different conformations in calmodulin and/or interact with different geometries relative to the antibody binding site. The anti-calmodulin monoclonal antibody should be useful for the purification of other calmodulin-dependent phosphodiesterases as well as isozymes of phosphorylase kinase.
...
PMID:Differential recognition of calmodulin-enzyme complexes by a conformation-specific anti-calmodulin monoclonal antibody. 302 48

A novel Mr 17,000 Ca2+-binding protein isolated from bovine brain was found to be a potent inhibitor of the Ca2+- and phospholipid-dependent protein kinase (protein kinase C), also isolated from bovine brain. Half-maximal inhibition by this calciprotein of the initial rate of phosphorylation of histone III-S by protein kinase C occurred at a calciprotein concentration of 2.2 microM under standard conditions. Comparison of the effects of a number of Ca2+-binding proteins on protein kinase C activity indicated that the Mr 17,000 Ca2+-binding protein was the most potent inhibitor, followed by the intestinal Ca2+-binding protein and calcineurin. Calmodulin, troponin C, S-100 protein and a Mr 21,000 Ca2+-binding protein of bovine brain were relatively weak inhibitors of protein kinase C. The inhibitory effect of the Mr 17,000 Ca2+-binding protein was apparently not due to its interaction with phospholipid or the basic protein substrate and therefore appears to be due to a direct effect on the protein kinase C. These observations suggest that the novel Mr 17,000 Ca2+-binding protein, and possibly other Ca2+-binding proteins, may play a physiological role in regulating the activity of protein kinase C.
...
PMID:Inhibition of the Ca2+- and phospholipid-dependent protein kinase by a novel Mr 17,000 Ca2+-binding protein. 316 Mar 47

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.
...
PMID:Dityrosine formation in calmodulin. 356 41

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.
...
PMID:Interaction of calmodulin with histones. Alteration of histone dephosphorylation. 625 89

The complete primary structure of the B subunit of calcineurin (protein phosphatase 2B) has been determined by automated sequence analysis. The protein consists of a single polypeptide chain of 168 residues, relative molecular mass 19200. The structure shows 35% identity with the sequence of calmodulin and 29% with troponin C. Homology is mainly confined to the regions of the four putative Ca2+-binding loops. The results demonstrate that the B subunit is a new member of this family of Ca2+-binding proteins. The N-terminal glycine residue is blocked with the C14-saturated fatty acid myristic acid and the first four residues are very similar to those of the catalytic subunit of cyclic-AMP-dependent protein kinase which also contains a myristoyl blocking group.
...
PMID:The structure of the B subunit of calcineurin. 632 Nov 84

The central effect of the Ca++ binding protein, calmodulin (CaM) on spontaneous feeding as well as on core temperature was examined in the satiated cat in which chronically indwelling cannulae were permanently implanted for intracerebroventricular (ICV) infusion. When CaM was injected ICV in doses of 2.5-10.0 micrograms, the intake of food was significantly enhanced in the satiated cat without any notable change in the animal's core temperature. Ca++ ions infused similarly in a solution of 6.25-25.0 mM also augmented the spontaneous ingestion of food, which was accompanied by a concentration-related decline in core temperature. When infused separately, neither CaM in a low dose (1.25 micrograms) nor Ca++ ions (3.0 mM) given ICV altered the intake of food of the satiated cat. However, the simultaneous infusion of CaM and Ca in these concentrations enhanced significantly the amount of food consumed by as much as 60 g. When the same concentration of Ca++ ions was infused ICV simultaneously with 5.0 micrograms troponin C, a Ca++ binding protein of an identical molecular weight, the intake of food was unaltered. Further, the spontaneous feeding induced by CaM could be attenuated either by the central chelation of Ca++ ions by 1.0-1.5 mM EGTA or by 30 micrograms calcineurin, a specific CaM inhibitor, when either was given ICV. Pre-treatment of the cat with ICV phentolamine (50 micrograms) also reduced the CaM-induced feeding response significantly, whereas the similar pre-treatment with ICV propranolol (50 micrograms) or naloxone (100 micrograms) failed to affect CaM-induced feeding behavior.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Calmodulin-induced feeding in the satiated cat: evidence for involvement of calcium and norepinephrine in the brain. 632 62

In the fasted cat, calmodulin (CaM) infused into the cerebral ventricle produces an increase in the normal intake of food in a dose-dependent manner. The enhancement of feeding by CaM seems to be functionally specific since the response was: (1) abolished by the simultaneous intraventricular infusion of calcineurin, a specific CaM antagonist; (2) not mimicked by another calcium binding protein, troponin C; and (3) independent of the CaM's lack of effect on body temperature and water intake. This finding opens up the dual possibility that this Ca2+ binding protein may affect receptors other than intracellularly and that CaM is involved in specific functions controlled by the brain.
...
PMID:Calmodulin infused intracerebroventricularly enhances food intake in the cat. 685 Mar 44

Calcium-dependent regulation of intracellular processes is mediated by proteins that on binding Ca2+ assume a new conformation, which enables them to bind to their specific target proteins and to modulate their function. Calmodulin (CaM) and troponin C, the two best characterized Ca2+-regulatory proteins, are members of the family of Ca2+-binding proteins utilizing the helix-loop-helix structural motif (EF-hand). Herzberg, Moult, and James (Herzberg, O., Moult, J., and James, M.N.G. (1986) J. Biol. Chem. 261, 2638-2644) proposed that the Ca2+-induced conformational transition in troponin C involves opening of the interface between the alpha-helical segments in the N-terminal domain of this protein. Here we have tested the hypothesis that a similar transition is the key Ca2+-induced regulatory event in calmodulin. Using site-directed mutagenesis we have substituted cysteine residues for Gln41 and Lys75 (CaM41/75) or Ile85 and Leu112 (CaM85/112) in the N-terminal and C-terminal domains, respectively, of human liver calmodulin. Based on molecular modeling, cysteines at these positions were expected to form intramolecular disulfide bonds in the Ca2+-free conformation of the protein, thus blocking the putative Ca2+-induced transition. We found that intramolecular disulfide bonds are readily formed in both mutants causing a decrease in affinity for Ca2+ and the loss of ability to activate target enzymes, phosphodiesterase and calcineurin. The regulatory activity is fully recovered in CaM41/75 and partially recovered in CaM85/112 upon reduction of the disulfide bonds with dithiothreitol and blocking the Cys residues by carboxyamidomethylation or cyanylation. These results indicate that the Ca2+-induced opening of the interfaces between helical segments in both domains of CaM is critical for its regulatory properties consistent with the Herzberg-Moult-James model.
...
PMID:Blocking the Ca2+-induced conformational transitions in calmodulin with disulfide bonds. 863 77


1 2 Next >>

---