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)

Phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha), which is one of the substrates of protein phosphatase 1 (PP1), occurs rapidly during the first minutes of post-ischemic reperfusion after an episode of cerebral ischemia. In the present work, two experimental models of transient global ischemia and ischemic tolerance (IT) were used to study PP1 interacting/regulatory proteins following ischemic reperfusion. For that purpose we utilized PP1 purified by microcystin chromatography, as well as 2D DIGE of PP1alpha and PP1gamma immunoprecipitates. The highest levels of phosphorylated eIF2alpha found after 30 min reperfusion in rats without IT, correlated with increased levels in PP1 immunoprecipitates of the inhibitor DARPP32 as well as GRP78 and HSC70 proteins. After 4 h reperfusion, the levels of these proteins in PP1c complexes had returned to control values, in parallel to a significant decrease in eIF2alpha phosphorylated levels. IT that promoted a decrease in eIF2alpha phosphorylated levels after 30 min reperfusion induced the association of GADD34 with PP1c, while prevented that of DARPP32, GRP78, and HSC70. Different levels of HSC70 and DARPP32 associated with PP1alpha and PP1gamma isoforms, whereas GRP78 was only detected in PP1gamma immunoprecipitates. Here we suggest that PP1, through different signaling complexes with their interacting proteins, may modulate the eIF2alpha phosphorylation/dephosphorylation during reperfusion after a transient global ischemia in the rat brain. Of particular interest is the potential role of GADD34/PP1c complexes after tolerance acquisition.
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PMID:Regulatory proteins of eukaryotic initiation factor 2-alpha subunit (eIF2 alpha) phosphatase, under ischemic reperfusion and tolerance. 1776 Aug 64

Since the beginning of organ transplantation, graft preservation has been one of the most important concerns. Ischemia reperfusion injury (IRI), which plays an important role in the quality and function of the graft, is a major cause for increased length of hospitalization and decreased long term graft survival. Among numerous attempts which have been made to minimize graft damage associated with IRI, the use of Thymoglobulin (TG) seems to offer potential benefits. TG is a polyclonal antibody which blocks multiple antigens related to IRI, in addition to its better known T cell depleting effects. This review will focus on the use of TG in preventing IRI in kidney transplantation (KTx) and liver transplantation (LTx). Different studies in experimental and clinical transplantation have shown that TG protects renal and liver grafts from IRI. Improvement in early graft function and decreased delayed graft function (DGF) rates are some of the clinical benefits of TG. Additionally, it is used in patients with hepatorenal syndrome to support the recovery of kidney function after LTx, by allowing reduced exposure to nephrotoxic calcineurin inhibitors as well as improving liver graft function by minimizing IRI. TG can reduce acute rejection rates in kidney and liver transplant recipients, decrease the length of hospital stay, and hence reduce transplantation costs. TG can play an important role in expanding the donor pool in both KTx and LTx by improving long-term graft and patient survival rates which increases the possibility of using marginal donors. Although controversial, the development of post-transplant lymphoproliferative disorder is a potential side effect of TG. No single optimal immunosuppressive regimen has given consistent results in decreasing the graft damage following IRI; however, TG usage in KTx and LTx appears to have some benefits in reducing IRI.
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PMID:Thymoglobulin and ischemia reperfusion injury in kidney and liver transplantation. 1789 Feb 65

The present study was aimed to investigate the effect of ischemic postconditioning (I-postC) on ischemia/reperfusion (I/R) injury and whether calreticulin (CRT) is involved in its intracellular signal transduction both in vivo and in cultured skeletal muscle cells. I/R injury in the right hind limb of healthy male Wistar rats was induced by clamping the right femoral artery, and the rats were randomly divided into 3 groups (n=16): I/R group (4-hour ischemia/12- or 24-hour reperfusion), ischemic preconditioning (IPC) group (3 cycles of 1-minute ischemia/1-minute reperfusion) and I-postC group (3 cycles of 5-minute reperfusion/5-minute ischemia). The left hind limb was used as control. Lactate dehydrogenase (LDH) activity in blood plasma, wet/dry weight ratio (W/D) and ultramicrostructure of skeletal muscle were detected 12 h or 24 h after reperfusion. Cultured skeletal muscle cells from neonatal Sprague-Dawley (SD) rat were divided into 6 groups: hypoxia/reoxygenation (H/R) group, hypoxic postconditioning (H-postC) group, hypoxic preconditioning (HPC) group, cyclosporine A (CsA) + H-postC group, CsA + H/R group and control group. H/R was produced by 2-hour hypoxia/24-hour reoxygenation. The survival rate and apoptotic rate of skeletal muscle cells in each group were measured. Western blot was used to detect the expressions of CRT and calcineurin (CaN). The results were as follows: (1) During in vivo experiment, compared with I/R, I-postC significantly decreased LDH activity and W/D, attenuated the ultramicrostructure injury of skeletal muscle and the apoptosis of nucleolus. 12 h and 24 h after reperfusion, compared with that in I/R group, the expression of CRT in I-postC group increased by 439% and 102%, respectively (P<0.05), and the expression of CaN increased by 196% and 63%, respectively (P<0.05). Correlation analysis indicated a positive correlation between CRT and CaN expressions (r=0.865, P<0.01). (2) In cultured skeletal muscle cells, H-postC attenuated cell injury induced by H/R. Compared with those in H/R group, CRT and CaN expressions in H-postC increased by 31.8% (P<0.05) and 6.02%, respectively. The protection of H-postC and CaN up-regulation were eliminated when CsA, the inhibitor of CaN, was added before H-postC. Both in vivo and in vitro results indicate that I-postC, similar as IPC, can protect the skeletal muscle against I/R injury, and its effects may be mediated by CRT and CaN up-regulation. The inhibition of CaN expression may also attenuate the protective effects of I-postC.
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PMID:[Calreticulin is involved in ischemic postconditioning-induced attenuation of ischemia/reperfusion injury in rat skeletal muscle]. 1794 Jul 5

N-myristoylation is a co-translational, irreversible addition of a fatty acyl moiety to the amino terminus of many eukaryotic cellular proteins. These myristoylated proteins in the cell have diverse biological functions such as signal transduction, cellular transformation and oncogensis. Known myristoylated proteins [Src family kinases, the catalytic subunit of cAMP-dependent protein kinase and calcineurin (CaN)] are either protein kinases or a protein phosphatases which modulate various cellular metabolic processes. Myristoylation is catalyzed by N-myristoyltransferase (NMT) and is recognized to be a widespread and functionally important modification of proteins. The main objective of this review is to focus on the potential role of NMT and CaN in epileptic brain and its involvement in neuronal apoptosis. The findings on the interaction of NMT and CaN with various signaling molecules in epileptic chickens adds to our understanding of the mechanism of CaN signaling in neuronal apoptosis. Understanding the regulation of NMT by specific inhibitors may help us to control the action of this enzyme on its specific substrates and may lead to improvements in the management of various neurological disorders like Alzheimer's disease, ischemia and epilepsy.
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PMID:Myristoyltransferase and calcineurin: novel molecular therapeutic target for epilepsy. 1799 6

Protein kinases and phosphatases can alter the impact of excitotoxicity resulting from ischemia by concurrently modulating apoptotic/survival pathways. Here, we show that protein phosphatase 1 (PP1), known to constrain neuronal signaling and synaptic strength (Mansuy et al., 1998; Morishita et al., 2001), critically regulates neuroprotective pathways in the adult brain. When PP1 is inhibited pharmacologically or genetically, recovery from oxygen/glucose deprivation (OGD) in vitro, or ischemia in vivo is impaired. Furthermore, in vitro, inducing LTP shortly before OGD similarly impairs recovery, an effect that correlates with strong PP1 inhibition. Conversely, inducing LTD before OGD elicits full recovery by preserving PP1 activity, an effect that is abolished by PP1 inhibition. The mechanisms of action of PP1 appear to be coupled with several components of apoptotic pathways, in particular ERK1/2 (extracellular signal-regulated kinase 1/2) whose activation is increased by PP1 inhibition both in vitro and in vivo. Together, these results reveal that the mechanisms of recovery in the adult brain critically involve PP1, and highlight a novel physiological function for long-term potentiation and long-term depression in the control of brain damage and repair.
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PMID:Protein phosphatase 1-dependent bidirectional synaptic plasticity controls ischemic recovery in the adult brain. 1817 33

Oxidative stress-induced cell death plays a major role in the progression of ischemic acute renal failure. Using microarrays, we sought to identify a stress-induced gene that may be a therapeutic candidate. Human proximal tubule (HK2) cells were treated with hydrogen peroxide (H2O2) and RNA was applied to an Affymetrix gene chip. Five genes were markedly induced in a parallel time-dependent manner by cluster analysis, including activating transcription factor 3 (ATF3), p21(WAF1/CiP1) (p21), CHOP/GADD153, dual-specificity protein phosphatase, and heme oxygenase-1. H2O2 rapidly induced ATF3 approximately 12-fold in HK2 cells and approximately 6.5-fold in a mouse model of renal ischemia-reperfusion injury. Adenovirus-mediated expression of ATF3 protected HK2 cells against H2O2-induced cell death, and this was associated with a decrease of p53 mRNA and an increase of p21 mRNA. Moreover, when ATF3 was overexpressed in mice via adenovirus-mediated gene transfer, ischemia-reperfusion injury was reduced. In conclusion, ATF3 plays a protective role in renal ischemia-reperfusion injury and the mechanism of the protection may involve suppression of p53 and induction of p21.
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PMID:ATF3 protects against renal ischemia-reperfusion injury. 1823 2

The N-methyl-D-aspartate receptor (NMDAR) is a Ca(2+)-permeable glutamate receptor mediating many neuronal functions under normal and pathological conditions. Ca(2+) influx via NMDARs activates diverse intracellular targets, including Ca(2+)-dependent protease calpain. Biochemical studies suggest that NR2A and NR2B subunits of NMDARs are substrates of calpain. Our physiological data showed that calpain, activated by prolonged NMDA treatment (100 microM, 5 min) of cultured cortical neurons, irreversibly decreased the whole-cell currents mediated by extrasynaptic NMDARs. Animals exposed to transient forebrain ischemia, a condition that activates calpain, exhibited the reduced NMDAR current density and the lower full-length NR2A/B level in a calpain-dependent manner. Disruption of the association between NMDARs and the scaffolding protein postsynaptic density (PSD)-95 facilitated the calpain regulation of synaptic NMDAR responses and NR2 cleavage in cortical slices, whereas inhibition of calcineurin activity blocked the calpain effect on NMDAR currents and NR2 cleavage. Calpain-cleaved NR2B subunits were removed from the cell surface. Moreover, cell viability assays showed that calpain, by targeting NMDARs, provided a negative feedback to dampen neuronal excitability in excitotoxic conditions. These data suggest that calpain activation suppresses NMDAR function via proteolytic cleavage of NR2 subunits in vitro and in vivo, and the susceptibility of NMDARs to calpain cleavage is controlled by PSD-95 and calcineurin.
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PMID:Postsynaptic density-95 (PSD-95) and calcineurin control the sensitivity of N-methyl-D-aspartate receptors to calpain cleavage in cortical neurons. 1844 9

It is well documented that exitotoxicity induced by N-methyl-D-aspartate (NMDA) receptor activation plays a pivotal role in delayed neuronal death in the hippocampal CA1 region after transient global ischemia. However, the effect of gamma-aminobutyric acid (GABA) receptor activation is uncertain in ischemia brain injury. The aim of this study was to investigate whether the enhancement of GABA receptor activity could inhibit NMDA receptor-mediated nitric oxide (NO) production by neuronal NO synthase (nNOS) in brain ischemic injury. The results showed that both the GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen had neuroprotective effect, and the combination of two agonists could significantly protect neurons against death induced by ischemia/reperfusion. Coapplication of muscimol with baclofen not only enhanced nNOS (Ser847) phosphorylation but also increased the interaction of nNOS with PSD95 at 6 hr and 1 day of reperfusion. Interestingly, the inhibitors of calcineurin and PP1/PP2A could enhance nNOS phosphorylation at Ser847 site at 1 day of reperfusion after ischemia but not at 6 hr of reperfusion. From these data, we conclude that GABA receptor activation could exert its neuroprotective effect through increasing nNOS (Ser847) phosphorylation by different mechanisms at 6 hr and 1 day of reperfusion. The increased interaction of nNOS and postsynaptic density-95 induced by GABA agonists is responsible for nNOS (Ser847) phosphorylation at both time points, but at 1 day of reperfusion the inhibition of protein phosphatase activity by GABA agonists also contributes to the neuroprotection. Our results suggest that GABA receptor agonists may serve as a potential and important neuroprotectant in therapy for ischemic stroke.
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PMID:Neuroprotection of gamma-aminobutyric acid receptor agonists via enhancing neuronal nitric oxide synthase (Ser847) phosphorylation through increased neuronal nitric oxide synthase and PSD95 interaction and inhibited protein phosphatase activity in cerebral ischemia. 1851 61

Calcineurin (CaN) is a calcium/calmodulin-dependent protein phosphatase that has an important role in ischemia-induced apoptosis. The serine/threonine kinase, Akt, which is also known as protein kinase B, has an important role in the cell death/survival pathways. Akt is activated by its phosphorylation, which is positively regulated by phosphatidylinositol 3-kinase (PI3K) and negatively regulated by a class of protein phosphatases (PPs) in tissue. However, the relationship between CaN and Akt after transient ischemia remains unclear. In the present study, we investigated whether CaN is involved in neuronal cell apoptosis and Akt dephosphorylation that occur during ischemic injury. We examined the interdependence between CaN and Akt/protein kinase B (PKB) in the rat retina after transient ischemia. After ischemic damage, we detected changes in levels of CaN, Akt and Bad in rats in the presence or absence FK506, CaN inhibitor. Our results show that CaN cleavage reduced Akt phosphorylation at Thr308 and Ser473, and led to apoptosis via dephosphorylation of the proapoptotic Bcl-2 family member Bad. After treatment with FK506, Akt and Bad dephosphorylation was greatly reduced. The total number of TUNEL-positive neurons was reduced by intravitreal injection of FK506 after transient ischemia. These results indicate that CaN cleavage negatively regulates Akt phosphorylation and is involved in retinal cell apoptosis after transient ischemia.
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PMID:Calcineurin mediates AKT dephosphorylation in the ischemic rat retina. 1870 31

To analyze the cardiac functions of AE3, we disrupted its gene (Slc4a3) in mice. Cl(-)/HCO3(-) exchange coupled with Na+-dependent acid extrusion can mediate pH-neutral Na+ uptake, potentially affecting Ca2+ handling via effects on Na+/Ca2+ exchange. AE3 null mice appeared normal, however, and AE3 ablation had no effect on ischemia-reperfusion injury in isolated hearts or cardiac performance in vivo. The NKCC1 Na+-K+-2Cl(-) cotransporter also mediates Na+ uptake, and loss of NKCC1 alone does not impair contractility. To further stress the AE3-deficient myocardium, we combined the AE3 and NKCC1 knock-outs. Double knock-outs had impaired contraction and relaxation both in vivo and in isolated ventricular myocytes. Ca2+ transients revealed an apparent increase in Ca2+ clearance in double null cells. This was unlikely to result from increased Ca2+ sequestration, since the ratio of phosphorylated phospholamban to total phospholamban was sharply reduced in all three mutant hearts. Instead, Na+/Ca2+ exchanger activity was found to be enhanced in double null cells. Systolic Ca2+ was unaltered, however, suggesting more direct effects on the contractile apparatus of double null myocytes. Expression of the catalytic subunit of protein phosphatase 1 was increased in all mutant hearts. There was also a dramatic reversal, between single null and double null hearts, in the carboxymethylation and localization to the myofibrillar fraction, of the catalytic subunit of protein phosphatase 2A, which corresponded to the loss of normal contractility in double null hearts. These data show that AE3 and NKCC1 affect Ca2+ handling, PLN regulation, and expression and localization of major cardiac phosphatases and that their combined loss impairs cardiac function.
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PMID:Impaired cardiac contractility in mice lacking both the AE3 Cl-/HCO3- exchanger and the NKCC1 Na+-K+-2Cl- cotransporter: effects on Ca2+ handling and protein phosphatases. 1877 25


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