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)

Neuronal and glial cell death caused by axonal injury sometimes contributes to whole brain pathology after traumatic brain injury (TBI). We show that neuroprotection by 2 types of immunosuppressants, cyclosporin A (CsA) and tacrolimus (FK506), in a cryogenic brain injury model results from inhibition of calcineurin and protection from mitochondrial damage caused by formation of a mitochondrial permeability transition pore induced by cyclophilin D (CyPD), one of the prolyl cis/trans isomerase family members. We evaluated why CsA is neuroprotective by microarray analysis of gene expression in the cryogenic brain injury rat model. Analyses of expression patterns demonstrated that expression of over 14,000 genes changed between the groups with and without CsA treatment, and about 350 genes among them were extracted showing a significant difference. We learned that the differential expression of several gene targets showed specific patterns in a time-dependent manner. These results may help elucidate the mechanisms of neuronal cell death after TBI and the neuroprotective effects of CsA after TBI.
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PMID:Search for novel gene markers of traumatic brain injury by time differential microarray analysis. 1667 47

Skeletal muscle is a highly adaptable tissue. It responds to environmental and physiological challenges by changes in size, fibre type and metabolism. All of these responses are underpinned by our genes and it is therefore generally assumed that genetic variation between individuals may account for the differences in musculature and athletic capabilities between people. Research into the genetic influences of our muscle is at an embryonic stage, but some early insight into potential regulators has recently emerged, which is reflected in this review. Broad heritability, which appears to affect muscle size and strength more than metabolism has been assessed in twin and sibling studies. It appears to account for more inter-individual variation in the young as opposed to older people. However, the studies reported to date do demonstrate a large degree of diversity, which is probably predominantly due to different methodological approaches being adopted as well as distinct populations being studied. At a molecular level, there has been enormous progress in identifying regulators of atrophy and hypertrophy though the study of knock-out and transgenic animals and also through the utilisation of cell culture models. Among others, the insulin-like growth factors, calcineurin, desmin, myf5, mrf4, MyoD and myogenin have been identified as positive regulators of muscle size, while TNF-alpha, myostatin and components of the ubiquitin pathway have been recognized as regulators of muscle wasting. However, given the ethical and mechanistic constraints of performing similar studies in humans, difficulties have arisen when attempting to translate the animal and cell culture findings to humans. However, the current search for target "exercise genes" in humans has yielded the first successful results. Variations in the genes encoding for: the angiotensin converting enzyme, alpha-actinin 3, bradykinin, ciliary neurotrophic factor, interleukin-15, insulin-like growth factor II, myostatin and the vitamin D-receptor have all been found to account for some of the inter-subject variability in muscle strength or size. However, the influences of these genetic variations are somewhat weak, and not always reproducible and furthermore they are predominantly based in young healthy people. Hence, a key topic, namely the molecular mechanisms of muscle frailty in the elderly still remains to be elucidated.
J Musculoskelet Neuronal Interact
PMID:Adaptive processes in skeletal muscle: molecular regulators and genetic influences. 1667 91

A number of neuronal functions, including synaptic plasticity, depend on proper regulation of synaptic proteins, many of which can be rapidly regulated by phosphorylation. Neuronal activity controls the function of these synaptic proteins by exquisitely regulating the balance of various protein kinase and protein phosphatase activity. Recent understanding of synaptic plasticity mechanisms underscores important roles that these synaptic phosphoproteins play in regulating both pre- and post-synaptic functions. This review will focus on key postsynaptic phosphoproteins that have been implicated to play a role in synaptic plasticity.
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PMID:Synaptic plasticity and phosphorylation. 1690 50

Synaptic growth is essential for the development and plasticity of neural circuits. To identify molecular mechanisms regulating synaptic growth, we performed a gain-of-function screen for synapse morphology mutants at the Drosophila neuromuscular junction (NMJ). We isolated a B' regulatory subunit of protein phosphatase 2A (PP2A) that we have named well-rounded (wrd). Neuronal overexpression of wrd leads to overgrowth of the synaptic terminal. Endogenous Wrd protein is present in the larval nervous system and muscle and is enriched at central and neuromuscular synapses. wrd is required for normal synaptic development; in its absence, there are fewer synaptic boutons and there is a decrease in synaptic strength. wrd functions presynaptically to promote normal synaptic growth and postsynaptically to maintain normal levels of evoked transmitter release. In the absence of wrd, the presynaptic cytoskeleton is abnormal, with an increased proportion of unbundled microtubules. Reducing PP2A enzymatic activity also leads to an increase in unbundled microtubules, an effect enhanced by reducing wrd levels. Hence, wrd promotes the function of PP2A and is required for normal cytoskeletal organization, synaptic growth, and synaptic function at the Drosophila NMJ.
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PMID:The B' protein phosphatase 2A regulatory subunit well-rounded regulates synaptic growth and cytoskeletal stability at the Drosophila neuromuscular junction. 1695 85

Neuronal L-type calcium channels contribute to dendritic excitability and activity-dependent changes in gene expression that influence synaptic strength. Phosphorylation-mediated enhancement of L-type channels containing the CaV1.2 pore-forming subunit is promoted by A-kinase anchoring proteins (AKAPs) that target cAMP-dependent protein kinase (PKA) to the channel. Although PKA increases L-type channel activity in dendrites and dendritic spines, the mechanism of enhancement in neurons remains poorly understood. Here, we show that CaV1.2 interacts directly with AKAP79/150, which binds both PKA and the Ca2+/calmodulin-activated phosphatase calcineurin (CaN). Cotargeting of PKA and CaN by AKAP79/150 confers bidirectional regulation of L-type current amplitude in transfected HEK293 cells and hippocampal neurons. However, anchored CaN dominantly suppresses PKA enhancement of the channel. Additionally, activation of the transcription factor NFATc4 via local Ca2+ influx through L-type channels requires AKAP79/150, suggesting that this signaling complex promotes neuronal L channel signaling to the nucleus through NFATc4.
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PMID:AKAP79/150 anchoring of calcineurin controls neuronal L-type Ca2+ channel activity and nuclear signaling. 1764 May 27

Neuronal calcium sensor (NCS) proteins regulate signal transduction and are highly conserved from yeast to humans. NCS homolog in fission yeast (Ncs1p) is essential for cell growth under extreme Ca(2+) conditions. Ncs1p expression increases approximately 100-fold when fission yeast grows in high extracellular Ca(2+) (>0.1 M). Here, we show that Ca(2+)-induced expression of Ncs1p is controlled at the level of transcription. Transcriptional reporter assays show that ncs1 promoter activity increased 30-fold when extracellular Ca(2+) was raised to 0.1 M and was highly Ca(2+)-specific. Ca(2+)-dependent transcription of ncs1 is abolished by the calcineurin inhibitor (FK506) and by knocking out the calcineurin target, prz1. Thus, Ca(2+)-induced expression of Ncs1p is linked to the calcineurin/prz1 stress response. The Ca(2+)-responsive ncs1 promoter region consists of 130 nucleotides directly upstream from the start codon and contains tandem repeats of the sequence, 5'-caact-3', that binds to Prz1p. The Ca(2+)-sensitive ncs1Delta phenotype is rescued by a yam8 null mutation, suggesting a possible interaction between Ncs1p and the Ca(2+) channel, Yam8p. Ca(2+) uptake and Ncs1p binding to yeast membranes are both decreased in yam8Delta, suggesting Ca(2+)-induced binding of Ncs1p to Yam8p results in channel closure. We propose that Ncs1p promotes Ca(2+) tolerance in fission yeast, in part by cytosolic Ca(2+) buffering and perhaps by negatively regulating the Yam8p Ca(2+) channel.
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PMID:Neuronal calcium sensor-1 (Ncs1p) is up-regulated by calcineurin to promote Ca2+ tolerance in fission yeast. 2001 64

Regucalcin was discovered in 1978 to be a calcium-binding protein that does not contain the EF-hand motif of the calcium-binding domain [M. Yamaguchi and T. Yamamoto, Chem. Pharm. Bull., 26, 1915-1918, 1978]. The regucalcin gene is localized on the X chromosome and its expression is enhanced through various transcription factors. Regucalcin is known to play a multifunctional role as a suppressor protein of cell signaling in many cell types. Regucalcin is expressed in rat brain neurons and it is decreased in the cerebral cortex and hippocampus of the brain with aging. Neuronal Ca(2+) signaling has been implicated in mechanisms of neuronal plasticity like long-term potentiation, which is likely to play an important role in learning and memory. The disturbance of brain Ca(2+) homeostasis may play a pivotal role in the revelation of brain disease. The intracellular Ca(2+) in brain tissues is increased with aging. Aging enhances the entry of Ca(2+) into brain neuronal cells across the plasma membranes. An increase in the brain microsomal Ca(2+)-ATPase activity of rats with aging resulted in calcium accumulation in the microsomes of the Ca(2+)-sequestrating system that is partly related to the brain toxicity by calcium. Regucalcin had an inhibitory effect on rat brain microsomal Ca(2+)-ATPase activity. The suppressive effect of regucalcin on brain microsomal Ca(2+)-ATPase activity was weakened in aged rats. Regucalcin was found to inhibit brain cytosolic protein kinase C. Brain microsomal Ca(2+)-ATPase activity was enhanced by protein kinase C in aged rats. Regucalcin could also inhibit activity of Ca(2+)/calmodulin-dependent protein kinase, protein phosphatase, and Ca(2+)/calmodulin-dependent nitric oxide synthase, which is linked to Ca(2+) signaling, in the cytosol of rat brain neurons. These inhibitory effects of regucalcin were weakened with aging. Regucalcin may play a pivotal role in the regulation of Ca(2+) signaling which is stimulated through a neurotransmitter in the brain neurons with aging.
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PMID:Role of regucalcin in brain calcium signaling: involvement in aging. 2265 98

Long-lasting changes in synaptic efficacy, such as those underlying long-term memory, require transcription. Activity-dependent transport of synaptically localized transcriptional regulators provides a direct means of coupling synaptic stimulation with changes in transcription. The CREB-regulated transcriptional coactivator (CRTC1), which is required for long-term hippocampal plasticity, binds CREB to potently promote transcription. We show that CRTC1 localizes to synapses in silenced hippocampal neurons but translocates to the nucleus in response to localized synaptic stimulation. Regulated nuclear translocation occurs only in excitatory neurons and requires calcium influx and calcineurin activation. CRTC1 is controlled in a dual fashion with activity regulating CRTC1 nuclear translocation and cAMP modulating its persistence in the nucleus. Neuronal activity triggers a complex change in CRTC1 phosphorylation, suggesting that CRTC1 may link specific types of stimuli to specific changes in gene expression. Together, our results indicate that synapse-to-nuclear transport of CRTC1 dynamically informs the nucleus about synaptic activity.
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PMID:Activity-dependent transport of the transcriptional coactivator CRTC1 from synapse to nucleus. 2277 Feb 21

Dynamin 1 is thought to mediate synaptic transmission through interactions with multiple endocytic accessory proteins in a phosphorylation-dependent manner. Previously, we have shown that DYRK1A, a chromosome 21-encoded kinase implicated in the mental retardation of Down syndrome, phosphorylates primarily serine 857 (S857) in the proline-rich domain, found only in 1xa, one of the alternative C-terminal splicing isoforms of dynamin 1. Dynamin 1xa and 1xb isoforms are able to assemble into heterologous complexes and are coregulated by DYRK1A phosphorylation in binding to amphiphysin in vitro. To help in assessing the physiological significance of S857 phosphorylation, we developed a semiquantitative method for measuring the cellular level of phospho-S857 (pS857). Dynamin 1xa is highly phosphorylated at S857 in resting hippocampal neurons and in a hippocampal cell line, with >60% of all endogenous protein phosphorylated at this residue. In the hippocampus, the level of pS857 is dynamically controlled by synaptic stimulations with the involvement of Ca(2+)/calcineurin and AMPA/kainate receptors. Immunofluorescence staining shows that pS857 is found in the soma and throughout the entire length of apical dendrites in resting pyramidal neurons. Neuronal stimulation in the Schaffer collateral pathway promotes pS857 dephosphorylation in distal areas of apical dendrites, the region forming synapses with the impinging axons of Schaffer collateral. In summary, our results support the conclusion that S857 phosphorylation is a physiological event and its level is modulated by neuronal activity in nerve terminals.
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PMID:Activity-dependent phosphorylation of dynamin 1 at serine 857. 2285 10

Neuronal N-methyl-D-aspartate subtype of ionotropic glutamate receptor (NMDAR) that plays essential roles in excitatory synaptic transmission is regulated by phosphorylation. However, the kinases and phosphatases involved in this regulation are not completely known. We show that the GluN2B subunit of NMDAR is phosphorylated at Ser(1303) by protein kinase C (PKC) and is dephosphorylated by protein phosphatase 1 (PP1), but not protein phosphatase 2A (PP2A) in isolated postsynaptic density (PSD). Although PSD is known to harbor PKC, PP1 and PP2A, their ability to regulate phosphorylation of GluN2B-Ser(1303) would depend on the accessibility of GluN2B-Ser(1303) to these proteins. Since PSD preparation is likely to maintain the organization of its component proteins as inside neurons, accessibility of kinases and phosphatases to GluN2B-Ser(1303)in vivo would be addressed by experiments using this system. Using an antibody specific for the phosphorylated state of GluN2B-Ser(1303) we demonstrate that PP1 is the major phosphatase in rat brain PSD that can dephosphorylate the GluN2B-Ser(1303) endogenous to PSD. We also show that PKC present in PSD can phosphorylate GluN2B-Ser(1303). The events reported here might be important in regulating GluN2B-Ser(1303) phosphorylation in vivo.
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PMID:Regulation of phosphorylation at Ser(1303) of GluN2B receptor in the postsynaptic density. 2298 38


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