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)

Mutations in the Drosophila calcineurin B2 gene cause the collapse of indirect flight muscles during mid stages of pupal development. Examination of cell fate-specific markers indicates that unlike mutations in genes such as vestigial, calcineurin B2 does not cause a shift in cell fate from indirect flight muscle to direct flight muscle. Genetic and molecular analyses indicate a severe reduction of myosin heavy chain gene expression in calcineurin B2 mutants, which accounts at least in part for the muscle collapse. Myofibrils in calcineurin B2 mutants display a variety of phenotypes, ranging from normal to a lack of sarcomeric structure. Calcineurin B2 also plays a role in the transition to an adult-specific isoform of troponin I during the late pupal stages, although the incompleteness of this transition in calcineurin B2 mutants does not contribute to the phenotype of muscle collapse. Together, these findings suggest a molecular basis for the indirect flight muscle hypercontractility phenotype observed in flies mutant for Drosophila calcineurin B2.
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PMID:Calcineurin function is required for myofilament formation and troponin I isoform transition in Drosophila indirect flight muscle. 1629 4

FHA domains adopt a beta-sandwich fold with 11 strands. The first evidence of partially unfolded forms of a beta-sandwich is derived from native-state hydrogen exchange (NHX) of the forkhead-associated (FHA) domain from kinase-associated protein phosphatase from Arabidopsis. The folding kinetics of this FHA domain indicate that EX2 behavior prevails at pH 6.3. In the chevron plot, rollover in the folding arm and bends in the unfolding arm suggest folding intermediates. NHX of this FHA domain suggests a core of six most stable beta-strands and two loops, characterized by rare global unfolding events. Flanking this stable core are beta-strands and recognition loops with less stability, termed subglobal motifs. These suggest partially unfolded forms (near-native intermediates) with two levels of stability. The spatial separation of the subglobal motifs on the flanks suggests possible parallelism in their folding as additional beta-strands align with the stable core of six strands. Intermediates may contribute to differences in stabilities and m-values suggested by NHX or kinetics relative to chemical denaturation. Residual structure in the unfolded regime is suggested by superprotection of beta-strand 6 and by GdmCl-dependence of adjustments in amide NMR spectra and residual optical signal. The global folding stability depends strongly on pH, with at least 3 kcal/mol more stability at pH 7.3 than at pH 6.3. This FHA domain is hypothesized to fold progressively with initial hydrophobic collapse of its stable six-stranded core followed by addition of less stable flanking beta-strands and ordering of recognition loops.
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PMID:Partially unfolded forms and non-two-state folding of a beta-sandwich: FHA domain from Arabidopsis receptor kinase-associated protein phosphatase. 1700 79

Osteonecrosis, the calcineurin-inhibitor-induced pain syndrome and transient marrow oedema may occur after renal transplantation, are generally painful and can be diagnosed by X-ray, radionuclide scan or magnetic resonance imaging. They share features of increased intraosseous pressure, compromised vascular supply, marrow oedema and the development of a 'bone compartment syndrome'. Glucocorticoid dosage is the most commonly implicated risk factor for osteonecrosis. Mechanisms may include the differentiation of mesenchymal stem cells to adipocytes causing increased intraosseous pressure and collapse of marrow sinusoids, as well as increased osteoblast and osteocyte apoptosis. Some of these effects may be ameliorated by lipid lowering drugs. Calcineurin-inhibitors, particularly cyclosporine, may increase the risk of osteonecrosis because of vasoconstrictive effects and sirolimus may influence the development of osteonecrosis by potentiating the effects of calcineurin inhibitors or by influencing the lipid profile. For osteonecrosis, early stages are generally managed conservatively or with core decompression sometimes accompanied by bone grafting and more recently the injection of bone morphogenic protein. The use of iloprost to improve blood flow and bisphosphonates and RANK-ligand inhibition to reduce osteoclastic resorption of remaining trabecular structures are as yet unproven strategies. Unfortunately, the rate of total hip arthroplasty remains high. For the calcineurin-inhibitor-induced pain syndrome and transient marrow oedema, calcium channel blockers, the reduction or withdrawal of calcineurin-inhibitors and core decompression have been used. Although a lack of randomized controlled trials makes management decisions difficult, early recognition of these bone pain syndromes affords the best opportunity for avoiding prolonged pain or joint replacement surgery.
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PMID:From marrow oedema to osteonecrosis: common paths in the development of post-transplant bone pain. 1719 98

Toxic cyanobacteria blooms in drinking water supplies have been an increasing public health concern all over the world. Human populations can be exposed to microcystins, an important family of cyanotoxins, mainly by oral ingestion. However, inhalation from recreational water and hemodialysis can represent other routes. This study investigated changes in respiratory mechanics, histology, protein phosphatase (PP) 1 and 2A activity and microcystin in lung of adult mice injected intraperitoneally (i.p.) with microcystin-LR. Thirty-six mice were divided into control (CTRL) and test (CYANO) groups. CTRL group received an i.p. injection of saline and the CYANO group received 40 microg MCYST-LR/kg i.p. After 2 and 8 h, and 1, 2 and 4 days after toxin injection, six mice from each group were sampled for analyses. Resistive and viscoelastic pressures, static and dynamic elastances augmented at 2 h in CYANO and so remained until day 4. Alveolar collapse and inflammatory cell infiltration were found 2h after the injection, reaching peak values at 8 h. However, no microcystin or inhibition of PPases could be detected in mice lungs. In conclusion, MCYST-LR led to a rapid increase in lung impedance and an inflammatory response with interstitial edema and inflammatory cell recruitment in mice.
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PMID:Effects of microcystin-LR on mouse lungs. 1752 92

Calcium plays a key role during growth cone collapse. Recently, it has been proposed that low- and high-amplitude rises in [Ca(2+)](i) result in the activation of the neurite outgrowth inhibiting proteins calcineurin and calpain, respectively. However, it remains unknown if and how these mechanisms are modulated by specific guidance cues. Here we report that the inhibitory cue Semaphorin 5B induces growth cone collapse by promoting the influx of extracellular Ca(2+). The resulting rise in [Ca(2+)](i) is characterized by a low-amplitude increase followed by a marked secondary rise, suggesting the potential involvement of both calcineurin and calpain. In support of this, inhibition of either effector attenuated Sema5B-induced collapse, a result that was augmented by the simultaneous inhibition of both targets. Furthermore, we provide evidence that Sema5B induces calpain-mediated cleavage of calcineurin. We thus show for the first time that ligand-induced growth cone collapse can activate both calcineurin- and calpain-mediated pathways concurrently.
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PMID:Combined activation of calpain and calcineurin during ligand-induced growth cone collapse. 1782 76

Liver disorders with a likely autoimmune pathogenesis in childhood include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplantation. AIH is divided into two subtypes according to seropositivity for smooth muscle and/or antinuclear antibody (SMA/ANA, type 1) or liver kidney microsomal antibody (LKM1, type 2). There is a female predominance in both. LKM1 positive patients tend to present more acutely, at a younger age, and commonly have partial IgA deficiency, while duration of symptoms before diagnosis, clinical signs, family history of autoimmunity, presence of associated autoimmune disorders, response to treatment, and long-term prognosis are similar in both groups. The most common type of paediatric sclerosing cholangitis is ASC. The clinical, biochemical, immunological, and histological presentation of ASC is often indistinguishable from that of AIH type 1. In both, there are high IgG, non-organ specific autoantibodies, and interface hepatitis. Diagnosis is made by cholangiography. Children with ASC respond to immunosuppression satisfactorily and similarly to AIH in respect to remission and relapse rates, times to normalization of biochemical parameters, and decreased inflammatory activity on follow up liver biopsies. However, the cholangiopathy can progress. There may be evolution from AIH to ASC over the years, despite treatment. De novo AIH after liver transplantation affects patients not transplanted for autoimmune disorders and is strikingly reminiscent of classical AIH, including elevated titres of serum antibodies, hypergammaglobulinaemia, and histological findings of interface hepatitis, bridging fibrosis, and collapse. Like classical AIH, it responds to treatment with prednisolone and azathioprine. De novo AIH post liver transplantation may derive from interference by calcineurin inhibitors with the intrathymic physiological mechanisms of T-cell maturation and selection. Whether this condition is a distinct entity or a form of atypical rejection in individuals susceptible to the development of autoimmune phenomena is unclear. Whatever its etiology, the recognition of this potentially life-threatening syndrome is important since its management differs from that of standard anti-rejection therapy.
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PMID:Autoimmune paediatric liver disease. 1852 33

A-kinase-anchoring protein 149 (AKAP149) is a membrane protein of the mitochondrial and endoplasmic reticulum/nuclear envelope network. AKAP149 controls the subcellular localization and temporal order of protein phosphorylation by tethering protein kinases and phosphatases to these compartments. AKAP149 also includes an RNA-binding K homology (KH) domain, the loss of function of which has been associated in other proteins with neurodegenerative syndromes. We show here that protein phosphatase 1 (PP1) binding occurs through a conserved RVXF motif found in the KH domain of AKAP149 and that PP1 and RNA binding to this same site is mutually exclusive and controlled through a novel, phosphorylation-dependent mechanism. A collapse of the mitochondrial network is observed upon introduction of RNA-binding deficient mutants of AKAP149, pointing to the importance of RNA tethering to the mitochondrial membrane by AKAP149 for mitochondrial distribution.
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PMID:Mutually exclusive binding of PP1 and RNA to AKAP149 affects the mitochondrial network. 1907 62

Glucose, in the absence of additional nutrients, induces programmed cell death in yeast. This phenomenon is independent of yeast metacaspase (Mca1/Yca1) and of calcineurin, requires ROS production and it is concomitant with loss of cellular K(+) and vacuolar collapse. K(+) is a key nutrient protecting the cells and this effect depends on the Trk1 uptake system and is associated with reduced ROS production. Mutants with decreased activity of plasma membrane H(+)-ATPase are more tolerant to glucose-induced cell death and exhibit less ROS production. A triple mutant ena1-4 tok1 nha1, devoid of K(+) efflux systems, is more tolerant to both glucose- and H(2)O(2)-induced cell death. We hypothesize that ROS production, activated by glucose and H(+)-ATPase and inhibited by K(+) uptake, triggers leakage of K(+), a process favoured by K(+) efflux systems. Loss of cytosolic K(+) probably causes osmotic lysis of vacuoles. The nature of the ROS-producing system sensitive to K(+) and H(+) transport is unknown.
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PMID:The role of K(+) and H(+) transport systems during glucose- and H(2)O(2)-induced cell death in Saccharomyces cerevisiae. 2021 54

The pluripotency of mouse embryonic stem cells (mESCs) is controlled by a network of transcription factors, mi-RNAs, and signaling pathways. Here, we present a new regulatory circuit that connects miR-335, Oct4, and the Retinoblastoma pathway to control mESC self-renewal and differentiation. Oct4 drives the expression of Nipp1 and Ccnf that inhibit the activity of the protein phosphatase 1 (PP1) complex to establish hyperphosphorylation of the retinoblastoma protein 1 (pRb) as a hallmark feature of self-renewing mESCs. The Oct4-Nipp1/Ccnf-PP1-pRb axis promoting mESC self-renewal is under control of miR-335 that regulates Oct4 and Rb expression. During mESC differentiation, miR-335 upregulation co-operates with the transcriptional repression of Oct4 to facilitate the collapse of the Oct4-Nipp1/Ccnf-PP1-pRb axis, pRb dephosphorylation, the exit from self-renewal, and the establishment of a pRb-regulated cell cycle program. Our results introduce Oct4-dependent control of the Rb pathway as novel regulatory circuit controlling mESC self-renewal and differentiation.
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PMID:An Oct4-pRb axis, controlled by MiR-335, integrates stem cell self-renewal and cell cycle control. 2330 55

Cyclosporin A (CSA) suppresses immune function by blocking the cyclophilin A and calcineurin/NFAT signaling pathways. In addition to immunosuppression, CSA has also been shown to have a wide range of effects in the cardiovascular system including disruption of heart valve development, smooth muscle cell proliferation, and angiogenesis inhibition. Circumstantial evidence has suggested that CSA might control Notch signaling which is also a potent regulator of cardiovascular function. Therefore, the goal of this project was to determine if CSA controls Notch and to dissect the molecular mechanism(s) by which CSA impacts cardiovascular homeostasis. We found that CSA blocked JAG1, but not Dll4 mediated Notch1 NICD cleavage in transfected 293T cells and decreased Notch signaling in zebrafish embryos. CSA suppression of Notch was linked to cyclophilin A but not calcineurin/NFAT inhibition since N-MeVal-4-CsA but not FK506 decreased Notch1 NICD cleavage. To examine the effect of CSA on vascular development and function, double transgenic Fli1-GFP/Gata1-RFP zebrafish embryos were treated with CSA and monitored for vasculogenesis, angiogenesis, and overall cardiovascular function. Vascular patterning was not obviously impacted by CSA treatment and contrary to the anti-angiogenic activity ascribed to CSA, angiogenic sprouting of ISV vessels was normal in CSA treated embryos. Most strikingly, CSA treated embryos exhibited a progressive decline in blood flow that was associated with eventual collapse of vascular luminal structures. Vascular collapse in zebrafish embryos was partially rescued by global Notch inhibition with DAPT suggesting that disruption of normal Notch signaling by CSA may be linked to vascular collapse. However, multiple signaling pathways likely cause the vascular collapse phenotype since both cyclophilin A and calcineurin/NFAT were required for normal vascular function. Collectively, these results show that CSA is a novel inhibitor of Notch signaling and vascular function in zebrafish embryos.
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PMID:Cyclosporin a disrupts notch signaling and vascular lumen maintenance. 2577 18


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