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)

We have investigated regional and temporal alterations in Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) and calcineurin (Ca2+/calmodulin-dependent protein phosphatase) after transient forebrain ischemia. Immunoreactivity and enzyme activity of CaM kinase II decreased in regions CA1 and CA3, and in the dentate gyrus, of the hippocampus early (6-12 h) after ischemia, but the decrease in immunoreactivity gradually recovered over time, except in the CA1 region. Furthermore, the increase in Ca2+/calmodulin-independent activity was detected up to 3 days after ischemia in all regions tested, suggesting that the concentration of intracellular Ca2+ increased. In contrast to CaM kinase II, as immunohistochemistry and regional immunoblot analysis revealed, calcineurin was preserved in the CA1 region until 1.5 days and then lost with the increase in morphological degeneration of neurons. Immunoblot analysis confirmed the findings of the immunohistochemistry. These results suggest that there is a difference between CaM kinase II and calcineurin in regional and temporal loss after ischemia and that imbalance of Ca2+/calmodulin-dependent protein phosphorylation-dephosphorylation may occur.
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PMID:Regional and temporal alterations in Ca2+/calmodulin-dependent protein kinase II and calcineurin in the hippocampus of rat brain after transient forebrain ischemia. 131 54

Dephosphorylation processes of target proteins are critical to the reversible regulation of intracellular signal transduction systems. Further, brain damage such as ischemic insult induces marked changes in protein kinase activity. To study these changes more thoroughly, specific monoclonal antibodies of the A and B subunits of calcineurin (protein phosphatase 2B) were raised, and regional alterations in the immunoreactivity of calcineurin in the rat hippocampus were investigated after a transient forebrain ischemic insult causing selective and delayed hippocampal CA1 pyramidal cell damage. In normal rats it was found that both the calcineurin A and the B subunits showed high immunoreactivity in the dendritic fields of the hippocampal formation. The immunoreactivity of subunit A in the strata oriens, the radiatum of the CA1 subfield and in the stratum lucidum of the CA3 subfield was most intense, whereas the immunoreactivity in the other CA3 subfields and in the dentate gyrus was relatively low. In contrast, the dendritic fields of the hippocampal formation were equally immunoreactive to calcineurin subunit B, although the stratum lucidum of the CA3, where the mossy fibers from the dentate granule cells terminate, showed a very high immunoreactivity of the B subunit. After transient forebrain ischemia in the CA1 subfield, where selective pyramidal cell death occurred two days after this ischemia, a marked loss of immunoreactivity in both subunits was observed, along with morphological pyramidal cell damage. A recovery of the immunoreactivity of A and B subunits in the strata oriens and radiatum was later noted 30 days after ischemia. In the stratum lucidum of the CA3, the immunoreactivity of both the A and B subunits was transiently depressed from 6 to 24 h, followed by a marked immunoreactivity enhancement from four to 30 days after ischemia. Further, in the histologically intact dentate gyrus, both the immunoreactivity of the A and B subunits in the molecular layer were transiently enhanced from four to 14 days after ischemia, particularly in the supragranular layer. The results clearly indicate that the protein dephosphorylation systems were markedly altered in the whole hippocampal formation during the recirculation period following ischemia. Further, the transient depression in the calcineurin immunoreactivity seen in the mossy fiber terminals may reflect modulated synaptic activity of the dentate granule cells, which may play a pivotal role in the delayed and selective death of the CA1 pyramidal cells. Thus, calcineurin appears to be an excellent marker enzyme for the detection of neuronal activity and synaptic plasticity after brain damage, such as an ischemic insult.
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PMID:Alteration in the immunoreactivity of the calcineurin subunits after ischemic hippocampal damage. 132 5

Sequential and regional changes in ischemic edema following various durations of focal cerebral ischemia were studied by magnetic resonance (MR) imaging in a rat unilateral intraluminal middle cerebral artery occlusion model. Occlusion was performed from 5 minutes to 5 hours. T2-weighted images were obtained chronologically 6 hours after onset of ischemia, on day 1 and day 7. An immunohistochemical study using antibodies to calcineurin and glial fibrillary acidic protein was performed to observe histological changes in the ischemic brain. The T2 high-signal-intensity areas representing ischemic edema were observed in the lateral striatum and/or the cerebral cortex by day 1 in all rats with 1- to 5-hour ischemia, and the areas were larger and detected earlier with longer durations of ischemia. In three of six rats with 15-minute ischemia and five of six rats with 30-minute ischemia, the T2 high-signal-intensity areas appeared transiently on day 1 in the dorsolateral striatum where loss of neurons expressing calcineurin immunoreactivity and associated gliosis were found. MR imaging in animal models of reversible focal ischemia can achieve sequential and noninvasive evaluation of dynamic regional changes in ischemic edema.
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PMID:Sequential changes in ischemic edema following transient focal cerebral ischemia in rats: magnetic resonance imaging study. 752 28

Calcium/calmodulin-dependent protein kinase II (kinase II) and protein phosphatase 2B (calcineurin) immunoreactivity in the rat hippocampus was studied 100 days after ischemic damage to hippocampal CA1 pyramidal neurons. One-hundred days after ischemia, only a few CA1 pyramidal neurons survived and they exhibited enhanced kinase II and calcineurin immunoreactivity in their basal and apical dendrites. The stratum lucidum of the CA3 (mossy fiber terminal area) had enhanced kinase II and calcineurin immunoreactivity. These results suggest activity-dependent regulation and redistribution of kinase II and calcineurin after intervention in neuronal circuitry.
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PMID:Calcium/calmodulin-dependent protein kinase II and protein phosphatase 2B (calcineurin) immunoreactivity in the rat hippocampus long after ischemia. 758 10

Glycogen is consumed during ischemic preconditioning and synthesized during the subsequent period of ischemic tolerance. To better understand this sequence, we examined the effect of brief coronary artery occlusions on regional myocardial glycogen metabolism in intact, anesthetized rats. Sequential 2-min periods of left coronary artery occlusion reduced the glycogen concentration of the anterior left ventricle approximately 30% relative to the posterior region. During subsequent reperfusion, the activity of the physiologically active glycogen synthase I form of glycogen synthase increased threefold in the anterior region (0.58 +/- 0.11 vs. 0.18 +/- 0.08 mumol.g-1.min-1, P < 0.01), stimulating a similar regional increase in glycogen synthesis rate (0.24 +/- 0.04 vs. 0.08 +/- 0.03 mumol.g-1.min-1, P < 0.01). These events were preceded by a rise in regional glucose 6-phosphate concentration, which increased the activity of a myocardial glycogen synthase phosphatase. In diabetic rats glycogen synthase phosphatase activity was significantly lower, and postischemic glycogen synthase activation was significantly impaired. These data suggest the operation of a feedback loop in which transient ischemia leads to a glucose 6-phosphate-mediated increase in the activity of a phosphoprotein phosphatase active toward glycogen synthase. This suggests phospho-protein phosphatase activation may be a feature of the preconditioned myocardium.
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PMID:Transient ischemia induces regional myocardial glycogen synthase activation and glycogen synthesis in vivo. 784 Feb 85

Protein phosphorylation represents a major post-translational mechanism through which numerous physiological processes are regulated. In the central nervous system, many extracellular messengers appear to exert their effects by regulating the intracellular concentration of specific second messengers which in turn activate specific phosphoprotein kinases. The diversity of these kinases and their substrates provide the means through which the diversity of brain cell types integrate and process extracellular signals. Increasing evidence indicates that specific phosphoproteins are involved in various aspects of brain development such as gene expression, protein synthesis, and cellular differentiation (e.g. growth cone formation, synaptogenesis). There are 3 essential components to all phosphorylation systems: 1) a specific protein kinase that, in the presence of ATP and Mg++, catalyzes the phosphorylation reaction; 2) a substrate protein that exists in either a phospho- or dephospho-form and 3) a protein phosphatase that catalyzes the removal of the phosphate group. All of these components represent putative targets for developmental neurotoxicants. In the adult nervous system, protein phosphorylation recently has been show to play a role in ischemia, neurodegenerative disease and specific neurotoxic exposures. Together, these observations provide the background for a discussion of the potential role of this key signal transduction system as a mediator of developmental neurotoxicity.
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PMID:A potential role for altered protein phosphorylation in the mediation of developmental neurotoxicity. 809 Mar 60

This study was designed to test the hypothesis that induction of the preconditioned state results in a sustained translocation of protein kinase C (PKC) which accounts for the memory associated with preconditioning. Isolated rabbit cardiomyocytes were subjected to established preconditioning protocols using either adenosine or transient ischemia. At timed intervals during induction of preconditioning (PC), post-incubation or final sustained ischemia, cells were harvested, subjected to digitonin lysis and separated into cytosolic and particulate fractions. Samples were evaluated by Western blot analysis with monoclonal antibodies to alpha, epsilon, zeta and gamma PKC isozymes, and bands were qualified by densitometry. Internal controls for each experiment included oxygenated cardiomyocytes and cell with PKC translocation evoked by treatment with phorbol 12-myristate 13-acetate (PMA). For control oxygenated cells, the particulate fraction contained about 30% of PKC epsilon, 5-10% of PKC alpha and 60-70% of PKC zeta. Preconditioning with adenosine (100 microM) or 10 min ischemia had no significant effect on these percentages. Furthermore, the relative amounts of PKC isozymes associated with the particulate fraction of control and preconditioned cells did not differ after a postincubation in oxygenated buffer or during a final ischemic incubation. PMA and ingenol completely translocated the epsilon and alpha isoforms, while thymeleatoxin totally translocated PKC alpha but only partially (50%) translocated PKC epsilon. The distribution of PKC zeta between fractions was not affected by any drug. The protein phosphatase inhibitor calyculin A protected cells mimicking preconditioning. This protection was blocked by preincubation with the selective PKC inhibitor calphostin C but was largely retained if calphostin C was added only during the final ischemic period. It is concluded that PKC activity is required for preconditioning, but a sustained translocation of PKC above basal levels is not necessary for protection of rabbit cardiomyocytes in vitro.
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PMID:Translocation of PKC, protein phosphatase inhibition and preconditioning of rabbit cardiomyocytes. 884 35

The effect of the immunosuppressant FK506 on ischaemic neuronal damage was studied in a rat model of transient cerebral ischemia induced by occlusion of both common carotid arteries in combination with hypotension for 10 min. Neuronal damage was assessed morphologically after 4 days of recovery. Treatment with FK506, given at a dose of 2 mg kg-1 by intraperitoneal injections 30 min prior to ischemia and once daily during recovery, decreased neuronal damage by 52% in the hippocampal CA1 region and by 48% in the temporal cortex. The protection was not due to diminished body temperature or a marked reduction of ischaemia-induced synaptic overflow of glutamate. We propose that FK506 decreases neuronal damage either by inhibiting calcineurin-mediated events or by preserving mitochondrial function.
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PMID:The immunosuppressant FK506 ameliorates ischaemic damage in the rat brain. 889 62

The effect of retrograde perfusion of the cerebral vein (RPCV) with antioxidant LY231617 on neuronal injury after transient ischemia in rat brain was examined. Transient ischemia was caused by left middle cerebral artery (MCA) occlusion and reperfusion. Rats were assigned to three groups: Group A (n = 6), MCA occlusion only; Group B (n = 8), RPCV with saline (flow rate 4.95 ml/hr) into the left inferior cerebral vein; and Group C (n = 6), RPCV with LY231617 (20 mg/kg/hr, flow rate 4.95 ml/hr). RPCV in Groups B and C was performed simultaneously with occlusion. Both occlusion and RPCV were performed for 30 minutes in awake animals. Seven days later, all rats were investigated for rotational behavior elicited by apomorphine (1.0 mg/kg), and then immunohistochemical analysis of brain specimens was carried out using calcineurin as a neuronal marker in the striatum to detect the ischemic damaged area. The number of turns to the left (lesioned side) in both Groups B (42 +/- 12) and C (46 +/- 14) was significantly lower (p < 0.01) than in Group A (222 +/- 45), but there was no significant difference between Groups B and C. The percentage ischemic damaged area in both Groups B (17.9 +/- 6.2%) and C (1.6 +/- 1.0%) was significantly less (p < 0.01) in Group A (51.1 +/- 2.1%). RPCV with and without LY231617 during occlusion was effective for attenuating reperfusion injury.
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PMID:Effectiveness of retrograde perfusion of the cerebral vein for attenuating neuronal injury after transient ischemia following reperfusion in the rat brain. 909 24

We examined the effects of FK506, a specific inhibitor of calcineurin, on the binding capacity of cyclic AMP-dependent protein kinase (cAMP-DPK) in gerbils subjected to 2-h cerebral hemispheric ischemia. FK506 (0.1 mg/kg) was infused intravenously at 15 min prior to the induction of ischemia by common carotid artery occlusion. The binding capacity of cAMP-DPK was evaluated by autoradiographic analysis of the cAMP binding, and cerebral blood flow (CBF) was measured by the [14C] iodoantipyrine method. In the sham-operated gerbils. FK506 significantly increased mean arterial blood pressure and tended to decrease CBF, suggesting that FK506 may constrict systemic blood vessels as well as cerebral blood vessels. On the other hand, cAMP binding was not altered by FK506 in the sham-operated gerbils. In the ischemia group of gerbils, FK506 prevented any significant reduction of cAMP binding in the hippocampus CA1 and cerebral cortices on the ischemic side, whereas it exerted no significant influence on the cAMP binding of the nonischemic side. The values of CBF were comparable between the vehicle-treated gerbils and FK506-treated gerbils in the ischemic regions. Preservation of cAMP binding indicates that intracellular signal transduction via cAMP-DPK can be maintained by FK506 despite ischemia, suggesting that this agent may be beneficial for reducing ischemic tissue damage.
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PMID:Calcineurin inhibitor, FK506, prevents reduction in the binding capacity of cyclic AMP-dependent protein kinase in ischemic gerbil brain. 914 23


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