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)

When platelets are stimulated by the addition of thrombin, a series of temporally linked signaling events are initiated. Some of the early events are needed to engage the integrin glycoprotein (GP) IIb-IIIa in a high-affinity state. This in turn leads to aggregation, which initiates a wave of events distinct from those triggered by thrombin. Platelet responses are sensitive to protein serine/threonine phosphatase inhibitors, but which events are dependent on protein phosphatase activity is not known. In the present studies, the effect of the phosphatase inhibitor calyculin A on aggregation-induced signaling was examined. The addition of 0.2 unit/mL thrombin caused aggregation-dependent redistribution of cytoskeletal proteins (actin binding protein, talin, vinculin, and alpha-actinin), glycoproteins (GPIIb-IIIa, PECAM), and signaling molecules (PI3-kinase, pp60c-src) to the cytoskeletal fraction of platelets. Addition of 1-2 microM calyculin A blocked the ability of 0.2 unit/mL thrombin to induce aggregation and the association of these molecules with the cytoskeleton. Aggregation (60-80% of control) was restored if 1 unit/mL thrombin was added, but there was no corresponding redistribution of actin binding protein, talin, vinculin, alpha-actinin, GPIIb-IIIa, PECAM, PI3-kinase, and pp60c-src to the cytoskeleton. Treatment of platelets with calyculin A resulted in an increase in the phosphorylation state of a membrane skeletal protein of 50 kDa. These data strongly suggest that platelet aggregation is dissociable from aggregation-induced signaling, which is dependent on type 1 and 2A phosphatase activities.
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PMID:Aggregation-dependent signaling in human platelets is sensitive to protein serine/threonine phosphatase inhibitors. 762 26

Microcystin-LR (MCLR) is a commonly encountered blue-green algal hepatotoxin and a known inhibitor of cellular protein phosphatase types 1 and 2A. The toxin causes alterations in, and redistribution of, intermediate filaments, microtubules, and actin microfilaments (MFs) in affected cells. In this study, the effect of MCLR on the sequence of alterations in MFs and actin-associated proteins (AAPs) of isolated hepatocytes was examined in an effort to determine whether morphologic changes induced in MFs by microcystins are a result of prior dislocation of AAPs. We studied the effects of MCLR exposure on alpha-actinin and talin, two AAPs that play a role in the orientation of the MFs. Primary hepatocytes were incubated with 10 microns MCLR for 0-64 min. The distribution of actin, alpha-actinin, and talin were examined using fluorescence microscopy. MCLR induced similar changes in the distribution of actin and the AAPs. Actin filament redistribution was first observed after 12 min of MCLR exposure, and was characterized by detachment of MFs from the cell periphery, followed by condensation at distinct focal points and progressive collapse into the interior of affected cells. Changes in alpha-actinin and talin distribution were first observed after 20 min of toxin exposure. The AAPs appeared to detach from focal contacts on the cytoplasmic surface of the plasma membrane, condense into cytoplasmic aggregates, and ultimately collapse into a juxtanuclear bundle. The results of this study indicate that, in hepatocytes exposed to MCLR, the collapse of actin MFs occurs prior to the dislocation of alpha-actinin and talin. Changes in these actin associated proteins are not likely to account for the initial changes in actin MFs.
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PMID:Effects of microcystin-LR on actin and the actin-associated proteins alpha-actinin and talin in hepatocytes. 861 2

We report a selective, differential stimulus-dependent enrichment of the actin-associated protein alpha-actinin and of isoforms of the signaling enzyme protein kinase C (PKC) in the neutrophil cytoskeleton. Chemotactic peptide, activators of PKC, and cell adhesion all induce a significant increase in the amount of cytoskeletal alpha-actinin and actin. Increased association of PKCbetaI and betaII with the cytoskeletal fraction of stimulated cells was also observed, with phorbol ester being more effective than chemotactic peptide. A fraction of phosphatase 2A was constitutively associated with the cytoskeleton independent of cell activation. None of the stimuli promoted association of vinculin or myosin II with the cytoskeleton. Phosphatase inhibitors okadaic acid and calyculin A prevented increases in cytoskeletal actin, alpha-actinin, and PKCbetaII induced by phorbol ester, suggesting the requirement for phosphatase activity in these events. Increases in cytoskeletal alpha-actinin and PKCbetaII showed differing sensitivity to agents that prevent actin polymerization (cytochalasin D, latrunculin A). Latrunculin A (1 microM) completely blocked PMA-induced increases in cytoskeletal alpha-actinin but reduced cytoskeletal recruitment of PKCbetaII only by 16%. Higher concentrations of latrunculin A (4 microM), which almost abolished the cytoskeletal actin pool, reduced cytoskeletal PKCbetaII by 43%. In conclusion, a selective enrichment of cytoskeletal and signaling proteins in the cytoskeleton of human neutrophils is induced by specific stimuli.
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PMID:Stimulus-induced selective association of actin-associated proteins (alpha-actinin) and protein kinase C isoforms with the cytoskeleton of human neutrophils. 1041 8

The calcium- and calmodulin-dependent protein phosphatase calcineurin has been implicated in the transduction of signals that control the hypertrophy of cardiac muscle and slow fiber gene expression in skeletal muscle. To identify proteins that mediate the effects of calcineurin on striated muscles, we used the calcineurin catalytic subunit in a two-hybrid screen for cardiac calcineurin-interacting proteins. From this screen, we discovered a member of a novel family of calcineurin-interacting proteins, termed calsarcins, which tether calcineurin to alpha-actinin at the z-line of the sarcomere of cardiac and skeletal muscle cells. Calsarcin-1 and calsarcin-2 are expressed in developing cardiac and skeletal muscle during embryogenesis, but calsarcin-1 is expressed specifically in adult cardiac and slow-twitch skeletal muscle, whereas calsarcin-2 is restricted to fast skeletal muscle. Calsarcins represent a novel family of sarcomeric proteins that link calcineurin with the contractile apparatus, thereby potentially coupling muscle activity to calcineurin activation.
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PMID:Calsarcins, a novel family of sarcomeric calcineurin-binding proteins. 1111 96

The Z-disc is a highly specialized multiprotein complex of striated muscles that serves as the interface of the sarcomere and the cytoskeleton. In addition to its role in muscle contraction, its juxtaposition to the plasma membrane suggests additional functions of the Z-disc in sensing and transmitting external and internal signals. Recently, we described two novel striated muscle-specific proteins, calsarcin-1 and calsarcin-2, that bind alpha-actinin on the Z-disc and serve as intracellular binding proteins for calcineurin, a calcium/calmodulin-dependent phosphatase shown to be integral in cardiac hypertrophy as well as skeletal muscle differentiation and fiber-type specification. Here, we describe an additional member of the calsarcin family, calsarcin-3, which is expressed specifically in skeletal muscle and is enriched in fast-twitch muscle fibers. Like calsarcin-1 and calsarcin-2, calsarcin-3 interacts with calcineurin, and the Z-disc proteins alpha-actinin, gamma-filamin, and telethonin. In addition, we show that calsarcins interact with the PDZ-LIM domain protein ZASP/Cypher/Oracle, which also localizes to the Z-disc. Calsarcins represent a novel family of sarcomeric proteins that serve as focal points for the interactions of an array of proteins involved in Z-disc structure and signal transduction in striated muscle.
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PMID:Calsarcin-3, a novel skeletal muscle-specific member of the calsarcin family, interacts with multiple Z-disc proteins. 1184 93

NMDA receptors are glutamate-sensitive ion channel receptors that mediate excitatory synaptic transmission and are widely implicated in synaptic plasticity and integration of synaptic activity in the CNS. This is in part attributable to the high calcium permeability of the ion channel, which allows receptor activation to influence the intracellular calcium concentration and also the slow time course of NMDA receptor-mediated synaptic currents. NMDA receptor activity is also regulated by the intracellular calcium concentration through activation of various calcium-dependent proteins, including calmodulin, calcineurin, protein kinase C, and alpha-actinin-2. Here, we have shown that calmodulin reduces the duration of native NMDA receptor single-channel openings from 3.5 +/- 0.6 msec to 1.71 +/- 0.2 msec in agreement with previous studies on recombinant NMDA receptors (Ehlers et al., 1996). NMDA receptor single-channel amplitudes and shut times were not affected. However, calmodulin reduced the duration of groups of channel openings called superclusters, which determine the slow time course of synaptic currents, from 121 +/- 25.4 msec to 60.4 +/- 11.6 msec. In addition, total open time, number of channel openings, and charge transfer per supercluster were all reduced by calmodulin. A 68% decrease in charge transfer per supercluster suggests that calmodulin activation will significantly reduce calcium influx during synaptic transmission. These results suggest that calmodulin-dependent inhibition of NMDA receptors will reduce the amplitude and time course of excitatory synaptic currents and thus affect synaptic plasticity and integration of synaptic activity in the CNS.
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PMID:Direct effects of calmodulin on NMDA receptor single-channel gating in rat hippocampal granule cells. 1238 92

Calcineurin, protein phosphatase 2B, is a calcium-binding protein that has been shown to modulate NMDA receptor activity (Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 369 (1994) 235; Regulation of glycine-insensitive desensitisation of the NMDA receptor in outside-out patches. J. Neurophysiol. 71 (1994) 754; Calcineurin acts via the C-terminus of NR2A to modulate desensitization of NMDA receptors. Neuropharmacology 42 (2002) 593) and synaptic transmission (Synaptic desensitization of NMDA receptors by calcineurin. Science 267 (1995) 1510; beta-adrenergic regulation of synaptic NMDA receptors by cAMP-dependent protein kinase. Neuron 16 (1996) 415). Calmodulin, a necessary co-factor for calcineurin (Calmodulin binding by calcineurin. J. Biol. Chem. 262 (1987) 15062), has also been shown to inhibit NMDA receptor activity (Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84 (1996) 745; Direct effects of calmodulin on NMDA receptor single-channel gating in rat hippocampal granule cells. J. Neurosci. 22 (2002) 8860) in a calcium dependent manner (Calmodulin mediates calcium-dependent inactivation of N-methyl-d-aspartate receptors. Neuron 21 (1998) 443; Interactions of calmodulin and alpha-actinin with the NR1 subunit modulate calcium-dependent inactivation of NMDA receptors. J. Neurosci. 19 (1999) 1165). In order to gain insight into the likely actions and interactions of calcineurin and calmodulin at excitatory synapses, we have investigated the effects of these two proteins on single NMDA receptor channel activity. Calcineurin and calmodulin are both known to reduce channel open time (Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 369 (1994) 235; Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84 (1996) 745), and the duration of receptor activations or superclusters. They are, therefore, predicted to shorten the synaptic current decay (Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 369 (1994) 235; Direct effects of calmodulin on NMDA receptor single-channel gating in rat hippocampal granule cells. J. Neurosci. 22 (2002) 8860). In agreement with Lieberman and Mody (Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 369 (1994) 235), the results of this study indicate calcineurin plus calmodulin reduces channel open time. However, this effect is not as pronounced as that observed in the presence of calmodulin alone. Calcineurin plus calmodulin was also found to increase single channel shut time. We conclude that in addition to its direct effects on single channel activity, calcineurin regulates the effects of calmodulin on NMDA receptor activity.
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PMID:Inhibitory interactions of calcineurin (phosphatase 2B) and calmodulin on rat hippocampal NMDA receptors. 1538 Mar 69

Calcineurin, which binds to the Z-disc in cardiomyocytes via alpha-actinin, promotes cardiac hypertrophy in response to numerous pathologic stimuli. However, the endogenous mechanisms regulating calcineurin activity in cardiac muscle are not well understood. We demonstrate that a muscle-specific F-box protein called atrogin-1, or muscle atrophy F-box, directly interacts with calcineurin A and alpha-actinin-2 at the Z-disc of cardiomyocytes. Atrogin-1 associates with Skp1, Cul1, and Roc1 to assemble an SCF(atrogin-1) complex with ubiquitin ligase activity. Expression of atrogin-1 decreases levels of calcineurin A and promotes its ubiquitination. Moreover, atrogin-1 attenuates agonist-induced calcineurin activity and represses calcineurin-dependent transactivation and NFATc4 translocation. Conversely, downregulation of atrogin-1 using adenoviral small interfering RNA (siRNA) expression enhances agonist-induced calcineurin activity and cardiomyocyte hypertrophy. Consistent with these cellular observations, overexpression of atrogin-1 in hearts of transgenic mice reduces calcineurin protein levels and blunts cardiac hypertrophy after banding of the thoracic aorta. These studies indicate that the SCF(atrogin-1) ubiquitin ligase complex interacts with and represses calcineurin by targeting calcineurin for ubiquitin-mediated proteolysis, leading to inhibition of cardiac hypertrophy in response to pathologic stimuli.
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PMID:Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex. 1548 53

Excitotoxic cell death (ECD) is characteristic of mammalian brain following min of anoxia, but is not observed in the western painted turtle following days to months without oxygen. A key event in ECD is a massive increase in intracellular Ca(2+) by over-stimulation of N-methyl-d-aspartate receptors (NMDARs). The turtle's anoxia tolerance may involve the prevention of ECD by attenuating NMDAR-induced Ca(2+) influx. The goal of this study was to determine if protein phosphatases (PPs) and intracellular calcium mediate reductions in turtle cortical neuron whole-cell NMDAR currents during anoxia, thereby preventing ECD. Whole-cell NMDAR currents did not change during 80 min of normoxia, but decreased 56% during 40 min of anoxia. Okadaic acid and calyculin A, inhibitors of serine/threonine PP1 and PP2A, potentiated NMDAR currents during normoxia and prevented anoxia-mediated attenuation of NMDAR currents. Decreases in NMDAR activity during anoxia were also abolished by inclusion of the Ca(2+) chelator -- BAPTA and the calmodulin inhibitor -- calmidazolium. However, cypermethrin, an inhibitor of the Ca(2+)/calmodulin-dependent PP2B (calcineurin), abolished the anoxic decrease in NMDAR activity at 20, but not 40 min suggesting that this phosphatase might play an early role in attenuating NMDAR activity during anoxia. Our results show that PPs, Ca(2+) and calmodulin play an important role in decreasing NMDAR activity during anoxia in the turtle cortex. We offer a novel mechanism describing this attenuation in which PP1 and 2A dephosphorylate the NMDAR (NR1 subunit) followed by calmodulin binding, a subsequent dissociation of alpha-actinin-2 from the NR1 subunit, and a decrease in NMDAR activity.
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PMID:Calcium and protein phosphatase 1/2A attenuate N-methyl-D-aspartate receptor activity in the anoxic turtle cortex. 1613 40

Calsarcins comprise a novel family of muscle-specific calcineurin-interacting proteins and play an important role in modulating both the function and substrate specificity of calcineurin in muscle cells. In this study, we cloned and characterized calsarcins from pig muscle. The deduced amino acid sequences of porcine calsarcin-1 (CS-1), calsarcin-2 (CS-2), and calsarcin-3 (CS-3) share the same putative calcineurin and alpha-actinin binding regions. Radiation hybrid mapping data indicate that CS-1 and CS-2 map to q2.1-2.5 of pig chromosome 8 (SSC8) and q2.4 of pig chromosome 14 (SSC14), respectively. The mRNA expressions of both CS-1 and CS-2 are regulated in skeletal muscle similarly during postnatal development but not during prenatal development, indicating differences in function, additionally demonstrated by minute differences in cellular localization within Pig Kidney Epithelial cells (PK15). We provide the first evidence that CS-1 is abundantly expressed in porcine heart and has an expression pattern similar to the human gene. This result suggests that the pig may be a suitable animal model to study the function of calsarcins in human heart disease.
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PMID:Characterization of different expression patterns of calsarcin-1 and calsarcin-2 in porcine muscle. 1657 46


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