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)

Atrial tachyarrhythmia (AF) alters intracellular calcium homeostasis and induces cellular hypertrophy of atrial myocytes. The impact of the calcium-dependent calcineurin pathway on the development of AF-induced atrial hypertrophy has not yet been analyzed. In this study, atrial tissue samples from patients with sinus rhythm and chronic persistent atrial fibrillation (CAF) were used to determine changes in expression and activity of calcineurin A (CnA), and its relation to CnA-regulated transcription factors NFATc1-4, and hypertrophic markers ANP, troponin I, and beta-MHC. CnA phosphatase activity and CnAbeta protein contents were significantly upregulated in patients with CAF. Calcineurin activation led to dephosphorylation, redistribution, and subsequent accumulation of NFATc3 in nuclei during CAF, and expression of hypertrophic genes was increased. CAF-dependent changes were reproduced by ex vivo pacing (2-4 Hz) of human atrial tissue slices. FK506 abolished the hypertrophic response induced by electrical-field stimulation. Atrial tachyarrhythmia causes atrial hypertrophy by activation of the CnA signal pathway, which thereby contributes to structural remodeling of human atria.
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PMID:Activation of the calcineurin signaling pathway induces atrial hypertrophy during atrial fibrillation. 1638 60

The transcription factor NFATc1 may be involved in slow skeletal muscle gene expression. NFATc1 translocates from cytoplasm to nuclei during slow fiber type electrical stimulation of skeletal muscle fibers because of activation of the Ca(2+)-dependent phosphatase calcineurin, resulting in nuclear factor of activated T-cells (NFAT) dephosphorylation and consequent exposure of its nuclear localization signal. Here, we find that unstimulated adult skeletal muscle fibers exhibit a previously unanticipated nucleocytoplasmic shuttling of NFATc1 without appreciable nuclear accumulation. In resting fibers, the nuclear export inhibitor leptomycin B caused nuclear accumulation of NFATc1 (but not of isoform NFATc3) and formation of NFATc1 intranuclear bodies independent of calcineurin. The rate of nuclear uptake of NFATc1 was 4.6 times lower in resting fibers exposed to leptomycin B than during electrical stimulation. Inhibitors of glycogen synthase kinase and protein kinase A or of casein kinase 1 slowed the decay of nuclear NFATc1 after electrical stimulation, but they did not cause NFATc1 nuclear uptake in unstimulated fibers. We propose that two nuclear translocation pathways, one pathway mediated by calcineurin activation and NFAT dephosphorylation and the other pathway independent of calcineurin and possibly independent of NFAT dephosphorylation, determine the distribution of NFATc1 between cytoplasm and nuclei in adult skeletal muscle.
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PMID:Activity- and calcineurin-independent nuclear shuttling of NFATc1, but not NFATc3, in adult skeletal muscle fibers. 1643 3

Kv4 channels are differentially expressed across the mouse left ventricular free wall. Accordingly, the transient outward K+ current (Ito), which is produced by Kv4 channels, is greater in left ventricular epicardial (EPI) than in endocardial (ENDO) cells. However, the mechanisms underlying heterogeneous Kv4 expression in the heart are unclear. Here, we tested the hypothesis that differential [Ca2+]i and calcineurin/NFATc3 signaling in EPI and ENDO cells contributes to the gradient of Ito function in the mouse left ventricle. In support of this hypothesis, we found that [Ca2+]i, calcineurin, and NFAT activity were greater in ENDO than in EPI myocytes. However, the amplitude of Ito was the same in ENDO and EPI cells when [Ca2+]i, calcineurin, and NFAT activity were equalized. Consistent with this, we observed complete loss of Ito and Kv4 heterogeneity in NFATc3-null mice. Interestingly, Kv4.3, Kv4.2, and KChIP2 genes had different apparent thresholds for NFATc3-dependent suppression and were ordered as Kv4.3 approximately KChIP2>Kv4.2. Based on these data, we conclude that calcineurin and NFATc3 constitute a Ca(2+)-driven signaling module that contributes to the nonuniform distribution of Kv4 expression, and hence Ito function, in the mouse left ventricle.
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PMID:Differential calcineurin/NFATc3 activity contributes to the Ito transmural gradient in the mouse heart. 1672 68

The calpain proteinases and their specific inhibitor calpastatin have been proposed to influence both the rates of myofibrillar protein turnover in vivo and meat tenderization postmortem. Elevated calpastatin concentrations in particular are associated with certain forms of hypertrophic growth and meat toughness. In the 5'region of the porcine calpastatin gene, there are 3 calpastatin promoters upstream of exons 1xa, 1xb, and 1u, respectively, each of which contain transcription factor-binding motifs, suggesting sensitivity to a variety of growth-promoting stimuli. This study examined the effect of the beta-adrenergic agonist clenbuterol and porcine ST (pST) treatment on calpastatin promoter usage in porcine LM in vivo using real-time PCR and also the responsiveness of transfected calpastatin promoter sequences to cyclic adenosine monophosphate (cAMP) and calcium (Ca2+)-related stimuli in reporter gene systems in cell studies. The effect of clenbuterol and pST on potential signaling pathways in vivo was also assessed by monitoring protein phosphatase 2B (calcineurin), NFATc3, calpain 3, IkappaB alpha, and NFkappaB by quantitative immunoblotting. Total calpastatin mRNA was increased by 52% (P < 0.05) after treatment with clenbuterol for 1 d and reduced by 35% (P < 0.01) after pST treatment for 7 d. Whereas clenbuterol had no significant differential effects on individual mRNA transcripts (types 1 to 3) derived from the 3 upstream promoters, pST significantly reduced all of these by 51, 39, and 40% (P < 0.001, 0.05, and 0.05), respectively. Promoter activity was increased in rat L6G8 cells transfected with a construct derived from exon 1u after treatment with dibutyryl cAMP (68%, P < 0.05) or forskolin (43%, P < 0.05), whereas 1xa activity was reduced by both of these agents (47 and 33%, respectively, P < 0.05). Treatment of cells with the calcium ionophore calcimycin reduced the activity of the 1u promoter by 40% (P < 0.01), with no effect on the other promoter constructs. Cyclosporin A had no effect on any promoter construct. The only signaling pathway component to be significantly altered by the in vivo treatments was calcineurin, which was decreased by 24% (P < 0.05) in clenbuterol-treated animals. In conclusion, 2 types of growth promoter in pigs had contrasting effects on calpastatin expression in LM. Transfected calpastatin promoters were differentially sensitive to cAMP- and Ca2+-related stimuli, in agreement with the proposed mode of action of the 2 growth promoters.
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PMID:Effect of anabolic agents on calpastatin promoters in porcine skeletal muscle and their responsiveness to cyclic adenosine monophosphate- and calcium-related stimuli. 1703 91

The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. Confocal immunofluorescence and Western blot analysis revealed that endothelin-1 efficiently increases NFATc3 nuclear accumulation in native arteries. Endothelin-1 also stimulates NFAT-dependent transcriptional activity, as shown by a luciferase reporter assay. Both the agonist-induced NFAT nuclear accumulation and transcriptional activity were prevented by the calcineurin inhibitor CsA and by the novel NFAT blocker A-285222. Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. Furthermore, by using small interfering RNA-mediated reduction of NFATc3, we show that this isoform is involved in the regulation of cell proliferation. Protein synthesis in intact arteries was investigated using autoradiography of [(35)S]methionine incorporation in serum-free culture. Inhibition of NFAT signaling did not affect overall protein synthesis or specifically the synthesis rates of major proteins associated with the contractile/cytoskeletal system. An intact contractile phenotype under these conditions was also shown by unchanged force response to depolarization or agonist stimulation. Our results demonstrate NFAT expression and activation in native human vessels and point out A-285222 as a powerful pharmacological blocker of NFAT signaling in the vasculature.
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PMID:Novel blocker of NFAT activation inhibits IL-6 production in human myometrial arteries and reduces vascular smooth muscle cell proliferation. 1707 31

Large conductance, Ca2+-activated K+ (BK) channels modulate the excitability and contractile state of arterial smooth muscle. Recently, we demonstrated that during hypertension, expression of the accessory beta1 subunit was decreased relative to the pore-forming alpha subunit of the BK channel. Reduced beta1 subunit expression resulted in BK channels with impaired function due to lowered sensitivity to Ca2+. Here, we tested the hypothesis that activation of the calcineurin/NFATc3 signaling pathway down-regulates beta1 expression during angiotensin II-induced hypertension. Consistent with this hypothesis, we found that in vivo administration of angiotensin II-activated calcineurin/NFATc3 signaling in arterial smooth muscle. During angiotensin II infusion, arterial smooth muscle BK channel function was decreased in wild type (WT) but not in NFATc3 null (NFATc3-/-) mice. Accordingly, beta1 expression was decreased in WT but not in NFATc3-/- arteries. Angiotensin II-induced down-regulation of the beta1 subunit required Ca2+ influx via L-type Ca2+ channels. However, in the absence of angiotensin II, moderate elevation of [Ca2+]i alone was not sufficient to activate NFAT transcriptional activity and, thus, decrease beta1 subunit expression. Importantly, angiotensin II infusion increased systemic blood pressure to a lower extent in NFATc3-/- than in WT mice, indicating that this transcription factor is required for the development of severe hypertension during chronic angiotensin II signaling activation. We conclude that activation of calcineurin and NFATc3 during sustained angiotensin II signaling down-regulates the expression of the beta1 subunit of the BK channel, which in turn contributes to arterial dysfunction and the development of hypertension.
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PMID:Activation of NFATc3 down-regulates the beta1 subunit of large conductance, calcium-activated K+ channels in arterial smooth muscle and contributes to hypertension. 1714 44

Skeletal muscle development and growth are regulated through multiple signaling pathways that include insulin-like growth factor I (IGF-I) and calcineurin activation of nuclear factor of activated T cell (NFAT) transcription factors. The developmental regulation and molecular mechanisms that control IGF-I gene expression in murine embryos and in differentiating C2C12 skeletal myocytes were examined. IGF-I is expressed in developing skeletal muscle, and its embryonic expression is significantly reduced in embryos lacking both NFATc3 and NFATc4. During development, the IGF-I exon 1 promoter is active in multiple organ systems, including skeletal muscle, whereas the alternative exon 2 promoter is expressed predominantly in the liver. The IGF-I exon 1 promoter flanking sequence includes two highly conserved regions that contain NFAT consensus binding sequences. One of these conserved regions contains a calcineurin/NFAT-responsive regulatory region that is preferentially activated by NFATc3 in C2C12 skeletal muscle cells and NIH3T3 fibroblasts. This NFAT-responsive region contains three clustered NFAT consensus binding sequences, and mutagenesis experiments demonstrated the requirement for two of these in calcineurin or NFATc3 responsiveness. Chromatin immunoprecipitation analyses demonstrated that endogenous IGF-I genomic sequences containing these conserved NFAT binding sequences interact preferentially with NFATc3 in C2C12 cells. Together, these experiments demonstrated that a NFAT-rich regulatory element in the IGF-I exon 1 promoter flanking region is responsive to calcineurin signaling and NFAT activation in skeletal muscle cells. The identification of a calcineurin/NFAT-responsive element in the IGF-I gene represents a potential mechanism of intersection of these signaling pathways in the control of muscle development and homeostasis.
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PMID:Developmental regulation of the mouse IGF-I exon 1 promoter region by calcineurin activation of NFAT in skeletal muscle. 1722 11

Calcineurin regulates the proliferation of many cell types through activation of the nuclear factor of activated T cells (NFAT). Two main isoforms of the calcineurin catalytic subunit [calcineurin A (CnA)alpha and CnAbeta] have been identified, although their expression and function are largely unknown in smooth muscle. Western blot analysis and confocal imaging were performed in freshly isolated and cultured rat aortic myocytes to identify these CnA isoforms and elucidate the effect of PDGF on their cellular distribution and interaction with NFAT isoforms. CnAalpha and CnAbeta isoforms displayed differential cellular distribution, with CnAalpha being evenly distributed between the nucleus and cytosol and CnAbeta being restricted to the cytosol. In contrast with the rat brain, we found no evidence for particulate/membrane localization of calcineurin. PDGF caused significant nuclear translocation of CnAbeta and induced smooth muscle cell proliferation, with both effects being abrogated by the calcineurin inhibitor cyclosporin A, the novel NFAT inhibitors A-285222 and inhibitor of NFAT-calcineurin association-6, and the adenylyl cyclase activator forskolin. PDGF also caused cyclosporin A-sensitive translocation of NFATc3, with no apparent effect on either CnAalpha or NFATc1 distribution. Moreover, approximately 87% of nuclear CnAbeta was found to colocalize with NFATc3, consistent with the finding that CnAbeta bound more avidly than CnAalpha to a glutathione S-transferase-NFATc3 fusion protein. Based on their differential distribution in aortic muscle, our results suggest that CnAalpha and CnAbeta are likely to have different cellular functions. However, CnAbeta appears to be specifically activated by PDGF, and we postulate that calcineurin-dependent nuclear translocation of NFATc3 is involved in smooth muscle proliferation induced by this mitogen.
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PMID:Nuclear translocation of calcineurin Abeta but not calcineurin Aalpha by platelet-derived growth factor in rat aortic smooth muscle. 1730 52

We previously reported that acetylcholinesterase plays a critical role in apoptosis and its expression is regulated by Ca(2+) mobilization. In the present study, we show that activated calpain, a cytosolic calcium-activated cysteine protease, and calcineurin, a calcium-dependent protein phosphatase, regulate acetylcholinesterase expression during A23187-induced apoptosis. The calpain inhibitor, calpeptin, and the calcineurin inhibitors, FK506 and cyclosporine A, inhibited acetylcholinesterase expression at both mRNA and protein levels and suppressed the activity of the human acetylcholinesterase promoter. In contrast, overexpression of constitutively active calcineurin significantly activated the acetylcholinesterase promoter. Furthermore, we identify a role for the transcription factor NFAT (nuclear factor of activated T cells), a calcineurin target, in regulating the acetylcholinesterase promoter during ionophore-induced apoptosis. Overexpression of human NFATc3 and NFATc4 greatly increased the acetylcholinesterase promoter activity in HeLa cells treated with A23187. Overexpression of constitutive nuclear NFATc4 activated the acetylcholinesterase promoter independent of A23187, whereas overexpression of dominant-negative NFAT blocked A23187-induced acetylcholinesterase promoter activation. These results indicate that calcineurin mediates acetylcholinesterase expression during apoptosis.
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PMID:Calcineurin mediates acetylcholinesterase expression during calcium ionophore A23187-induced HeLa cell apoptosis. 1732 Feb 3

Physiological responses to chronic hypoxia include polycythemia, pulmonary arterial remodeling, and vasoconstriction. Chronic hypoxia causes pulmonary arterial hypertension leading to right ventricular hypertrophy and heart failure. During pulmonary hypertension, pulmonary arteries exhibit increased expression of smooth muscle-alpha-actin and -myosin heavy chain. NFATc3 (nuclear factor of activated T cells isoform c3), which is aCa(2+)-dependent transcription factor, has been recently linked to smooth muscle phenotypic maintenance through the regulation of the expression of alpha-actin. The aim of this study was to determine if: (a) NFATc3 is expressed in murine pulmonary arteries, (b) hypoxia induces NFAT activation, (c) NFATc3 mediates the up-regulation of alpha-actin during chronic hypoxia, and (d) NFATc3 is involved in chronic hypoxia-induced pulmonary vascular remodeling. NFATc3 transcript and protein were found in pulmonary arteries. NFAT-luciferase reporter mice were exposed to normoxia (630 torr) or hypoxia (380 torr) for 2, 7, or 21 days. Exposure to hypoxia elicited a significant increase in luciferase activity and pulmonary arterial smooth muscle nuclear NFATc3 localization, demonstrating NFAT activation. Hypoxia induced up-regulation of alpha-actin and was prevented by the calcineurin/NFAT inhibitor, cyclosporin A (25 mg/kg/day s.c.). In addition, NFATc3 knock-out mice did not showed increased alpha-actin levels and arterial wall thickness after hypoxia. These results strongly suggest that NFATc3 plays a role in the chronic hypoxia-induced vascular changes that underlie pulmonary hypertension.
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PMID:NFATc3 mediates chronic hypoxia-induced pulmonary arterial remodeling with alpha-actin up-regulation. 1740 61


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