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

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

The frequency-dependent long-term modifications of pharmacologically isolated N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic potential (EPSPNMDA) was studied. Intracellular recordings were obtained from CA1 cells of rat hippocampal slices and in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM) and bicuculline (20 microM) which block non-NMDA and GABAA receptors, respectively. Low-frequency stimulation at 5 Hz resulted in a long-term depression (LTD) of EPSPNMDA in 12 of 17 cells. However, when the stimulus frequency was increased to 30 Hz, a long-term potentiation (LTP) of EPSPNMDA was observed in 7 out of 9 cells. The LTD was not affected by pretreating the slices with okadaic acid (0.5-1 microM) suggesting that activation of endogenous protein phosphatase is not responsible for this process. In the presence of L-2-amino-3-phosphonopropionic acid (50 microM) or (RS)-alpha-methyl-4-carboxyphenylglycine (200 microM), 5 Hz tetanization resulted in LTP instead of LTD. These results suggest that activation of metabotropic glutamate receptor (mGluR) is necessary for the induction of EPSPNMDA LTD and blockade of mGluR unmasks a LTP.
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PMID:The involvement of metabotropic glutamate receptors in long-term depression of N-methyl-D-aspartate receptor-mediated synaptic potential in the rat hippocampus. 775 92

Mechanisms of regulation of GABAA receptor function by intracellular calcium ([Ca2+]i) were examined in cell somata and apical dendrites of pyramidal cells, acutely dissociated from the CA1 hippocampal subfield of adult guinea-pigs. GABAA receptor-mediated currents were measured by whole-cell clamp recordings. N-methyl-D-aspartate receptor-mediated currents were used as conditioning source of calcium influx. Peak amplitudes of somatic GABAA whole-cell currents were reduced to about 15% of control values when net inward charge accumulation by N-methyl-D-aspartate currents reached 1.85 nC. A similar decline of GABAA currents was observed in dendritic recordings. The N-methyl-D-aspartate-mediated reduction of somatic and dendritic GABAA currents was accompanied by a well correlated decrease in peak and chord conductances. Pharmacological blockade of N-methyl-D-aspartate currents by 2-amino-5-phosphonopentanoic acid prevented the N-methyl-D-aspartate-mediated suppression of GABAA responses. The N-methyl-D-aspartate effect was mediated by the calcium component of N-methyl-D-aspartate receptor-mediated currents as demonstrated by a lack of effect in the absence of extracellular calcium and faster N-methyl-D-aspartate-mediated suppression of GABAA responses in lower intracellular 1,2-bis(2-aminophenoxy)ethane-N,N,N',N"-tetra-acetate. N-methyl-D-aspartate-mediated suppression of GABAA currents was significantly less expressed when intracellular ATP was replaced by its analog adenosine 5'-O-(3-thiotriphosphate) and when the specific phosphatase 2B inhibitor cypermethrin was added intracellularly. The reduction of GABAA responses persisted after cessation of N-methyl-D-aspartate-mediated calcium influx, indicating a long-term action of N-methyl-D-aspartate on GABAA responses. Voltage-activated calcium currents did not affect GABAA responses under the experimental conditions applied. In conclusion, the data presented show that calcium influxes through N-methyl-D-aspartate receptor channels result in long-term suppression of GABAA receptor function in CA1 pyramidal cells. Intracellular mechanisms of N-methyl-D-aspartate-mediated reduction of GABAA conductances involve activation of phosphatase 2B and consecutive dephosphorylation of the GABAA receptor or a closely associated GABAA receptor-regulating enzyme. Possible mechanisms of such a distinct N-methyl-D-aspartate-dependent calcium signalling pathway in the dephosphorylation-dependent suppression or GABAA receptor function are discussed.
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PMID:Impairment of GABAA receptor function by N-methyl-D-aspartate-mediated calcium influx in isolated CA1 pyramidal cells. 787 Mar 9

The induction of long-term potentiation (LTP) in the CA1 region of the hippocampus is mediated by N-methyl-D-aspartate (NMDA) receptor-coupled calcium influx. In addition, calcium/calmodulin (CaM) has been demonstrated to play an essential role in the induction process. In the present study, a possible role of CaM-dependent phosphatase (phosphatase 2B, PP-2B, calcineurin) in the LTP process was examined by intracellular recordings in apical dendrites of CA1 pyramidal cells of adult guinea-pigs. In dendrites in which cypermethrin, a potent and specific inhibitor of PP-2B (IC50 40 pM), was intracellularly applied, tetanization generated only short-term increases (15-30 min) of excitatory responses. In the intracellular presence of allethrin, a weak inhibitor of PP-2B, LTP expression was not affected. These findings demonstrate that activation of PP-2B is a necessary condition for the expression of LTP in CA1 pyramidal cell dendrites.
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PMID:Inhibition of phosphatase 2B prevents expression of hippocampal long-term potentiation. 788 Oct 62

We have investigated the effects of inhibitors of protein kinases and protein phosphatases on the NMDA receptor-independent potentiation of evoked and miniature (m) excitatory postsynaptic currents (EPSCs) induced by the entry of Ca2+ via voltage-gated Ca2+ channels in hippocampal CA1 pyramidal neurons. Voltage pulse-induced potentiation was markedly attenuated when evoked in the presence of the protein kinase blockers KN-62, K-252a, or H-7. Bath application of the protein phosphatase inhibitor calyculin A converted the usual transient potentiation of both evoked and spontaneous EPSCs induced by voltage pulses into a more sustained potentiation. Similarly, the introduction of the phosphatase inhibitors microcystin LR or okadaic acid into postsynaptic cells, via patch pipettes, also resulted in a sustained increase in the amplitude of mEPSCs. We propose that entry of Ca2+ into CA1 neurons activates calcium/calmodulin-dependent protein kinase II, which leads to an enhanced responsiveness of synaptic AMPA receptor channels. The enhancement is transient, however, owing to postsynaptic phosphatase activity.
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PMID:A role for protein kinases and phosphatases in the Ca(2+)-induced enhancement of hippocampal AMPA receptor-mediated synaptic responses. 791 94

We have studied the effect of brief (50-150 s) applications of N-methyl-D-aspartate (10-100 microM) on the phosphorylated state of the microtubule-associated protein 2 in slices of rat hippocampus. Following a similar experimental protocol we also studied the pattern of excitatory postsynaptic potentials intracellularly recorded in CA1 pyramidal cells elicited by stimulation of the Schaffer collateral-commissural pathway. N-Methyl-D-aspartate treatment produced a marked and specific dephosphorylation of the cytoskeletal microtubule-associated protein 2, which was not due to enhanced proteolytic activity. Dephosphorylation of the microtubule-associated protein 2 affects mainly the tubulin-binding domain of the molecule and seems to be a consequence of the activation of the Ca2+/calmodulin-dependent phosphatase calcineurin, as it is partially inhibited by calmidazolium but not by okadaic acid. A few minutes after N-methyl-D-aspartate treatment we observed a 23 +/- 17% increase in the amplitude of the monosynaptic excitatory postsynaptic potential recorded in the cells and the appearance of a large polysynaptic excitatory postsynaptic potential. Both effects lasted for several tens of minutes. The late polysynaptic potential was not observed when the CA3 and CA1 subfields were surgically separated. Our results indicate that the N-methyl-D-aspartate receptor activation leads to the dephosphorylation of the microtubule-associated protein 2 via a Ca2+/calmodulin phosphatase, probably calcineurine. This may, in turn, participate in the potentiation of synaptic efficacy.
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PMID:N-methyl-D-aspartate stimulates the dephosphorylation of the microtubule-associated protein 2 and potentiates excitatory synaptic pathways in the rat hippocampus. 839 39

The effectiveness of long-term potentiation (LTP) as a mechanism for information storage would be severely limited if processes that decrease synaptic strength did not also exist. In area CA1 of the rat hippocampus, prolonged periods of low-frequency afferent stimulation elicit a long-term depression (LTD) that is specific to the stimulated input. The induction of LTD was blocked by the extracellular application of okadaic acid or calyculin A, two inhibitors of protein phosphatases 1 and 2A. The loading of CA1 cells with microcystin LR, a membrane-impermeable protein phosphatase inhibitor, or calmodulin antagonists also blocked or attenuated LTD. The application of calyculin A after the induction of LTD reversed the synaptic depression, suggesting that phosphatase activity is required for the maintenance of LTD. These findings indicate that the synaptic activation of protein phosphatases plays an important role in the regulation of synaptic transmission.
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PMID:An essential role for protein phosphatases in hippocampal long-term depression. 839 1

MKP-1 (also known as CL100, 3CH134, Erp, and hVH-1) exemplifies a class of dual-specificity phosphatase able to reverse the activation of mitogen-activated protein (MAP) kinase family members by dephosphorylating critical tyrosine and threonine residues. We now report the cloning of MKP-3, a novel protein phosphatase that also suppresses MAP kinase activation state. The deduced amino acid sequence of MKP-3 is 36% identical to MKP-1 and contains the characteristic extended active-site sequence motif VXVHCXXGXSRSXTXXXAYLM (where X is any amino acid) as well as two N-terminal CH2 domains displaying homology to the cell cycle regulator Cdc25 phosphatase. When expressed in COS-7 cells, MKP-3 blocks both the phosphorylation and enzymatic activation of ERK2 by mitogens. Northern analysis reveals a single mRNA species of 2.7 kilobases with an expression pattern distinct from other dual-specificity phosphatases. MKP-3 is expressed in lung, heart, brain, and kidney, but not significantly in skeletal muscle or testis. In situ hybridization studies of MKP-3 in brain reveal enrichment within the CA1, CA3, and CA4 layers of the hippocampus. Metrazole-stimulated seizure activity triggers rapid (<1 h) but transient up-regulation of MKP-3 mRNA in the cortex, piriform cortex, and some amygdala nuclei. Metrazole stimulated similar regional up-regulation of MKP-1, although this was additionally induced within the thalamus. MKP-3 mRNA also undergoes powerful induction in PC12 cells after 3 h of nerve growth factor treatment. This response appears specific insofar as epidermal growth factor and dibutyryl cyclic AMP fail to induce significant MKP-3 expression. Subcellular localization of epitope-tagged MKP-3 in sympathetic neurons reveals expression in the cytosol with exclusion from the nucleus. Together, these observations indicate that MKP-3 is a novel dual-specificity phosphatase that displays a distinct tissue distribution, subcellular localization, and regulated expression, suggesting a unique function in controlling MAP kinase family members. Identification of a second partial cDNA clone (MKP-X) encoding the C-terminal 280 amino acids of an additional phosphatase that is 76% identical to MKP-3 suggests the existence of a distinct structurally homologous subfamily of MAP kinase phosphatases.
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PMID:MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase. 862 80


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