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

---

Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During ischemic stroke, massive neural damage occurs due to excess release of glutamate which acts mainly through N-methyl-D-aspartate (NMDA) receptors. Activation of the NMDA receptor stimulates nitric oxide (NO) production by NO synthase (NOS). NO mediates glutamate neurotoxicity as inhibitors of NOS prevent neuronal death. FK506, an immunosuppressant drug, binds to FK506 binding protein (FKBP). One target of the FK506/FKBP complex is the calcium/calmodulin-dependent protein phosphatase calcineurin, whose activity is inhibited upon interaction with FK506/FKBP. FK506 treatment increases phosphorylation level of calcinurin substrates including NOS. As a potent neuroprotective agent in vitro and in vivo, FK506 increases NOS phosphorylation and decreases NO production. NO activates poly(ADP-ribose) synthetase (PARS), a nuclear enzyme that synthesizes poly(ADP-ribose) from NAD. Prolonged activation of PARS depletes NAD and lowers cellular energy levels. Inhibition of PARS also prevents NO toxicity. NOS inhibitors, immunosuppressants and PARS inhibitors may be useful agents to prevent neuronal damage during stroke.
...
PMID:Nitric oxide synthase, immunophilins and poly(ADP-ribose) synthetase: novel targets for the development of neuroprotective drugs. 747 44

The immunosuppressive macrolide FK-506 has been shown to protect neurons in culture against glutamate excitotoxicity. This effect was attributed to the binding of immunosuppressants to calcineurin-inhibiting immunophilins. We now report that also the non-immunosuppressive macrolide antibiotics protect neurons in culture against NMDA- but not kainate-mediated excitotoxicity. The effect was structure-dependent: larger macrolide rings were more active. Macrolides did not affect the 3-(2-carboxypiperazin-4yl)-propyl-1-phosphonic acid (CPP) binding or the NMDA-mediated calcium influx.
...
PMID:Macrolide antibiotics protect neurons in culture against the N-methyl-D-aspartate (NMDA) receptor-mediated toxicity of glutamate. 750 70

Activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor increases levels of intracellular calcium and can lead to stimulation of protein kinase C activity. Several reports have demonstrated that stimulation of protein kinase C can, in turn, increase electrophysiological responses to NMDA in certain cells or in oocytes expressing certain NMDA receptor subunits. In the present study, the effects of protein kinase C activation on NMDA receptor-mediated increases in intracellular Ca2+ level were investigated in primary cultures of rat cerebellar granule cells using fura-2 fluorescence spectroscopy. Pretreatment of the cells with the protein kinase C activator phorbol 12-myristate 13-acetate (PMA), but not the inactive analogue 4 alpha-phorbol 12-myristate 13-acetate, inhibited NMDA-induced increases in intracellular Ca2+ levels. Coincubation of cells with PMA and the kinase inhibitor staurosporine or calphostin C blocked the PMA effect. The potency of NMDA was reduced twofold, and the potency of the NMDA receptor co-agonist, glycine, to enhance the response to NMDA was decreased fourfold by pretreatment of cells with PMA. The effect on glycine was mimicked by pretreatment with okadaic acid, a protein phosphatase inhibitor. PMA treatment did not significantly alter Mg2+ inhibition of the NMDA response but decreased the potency of the competitive antagonist CGS-19755. These data suggest that, in cerebellar granule cells, the function of the NMDA receptor may be subject to feed-back inhibition by protein kinase C stimulation. Under physiological conditions, this inhibition may result from a decreased effectiveness of the endogenous co-agonists, glutamate and glycine.
...
PMID:Protein kinase C activation attenuates N-methyl-D-aspartate-induced increases in intracellular calcium in cerebellar granule cells. 751 17

Protein kinases modulate the activity of several ligand-gated ion channels, including the NMDA (N-methyl-D-aspartate) subtype of glutamate receptor. Although phosphorylation and dephosphorylation of glutamate receptors may participate in several lasting physiological and pathological alterations of neuronal excitability, the physiological control of this cycle for NMDA channels has not yet been established. Using cell-attached recordings in acutely dissociated adult rat dentate gyrus granule cells, we now demonstrate that inhibitors of an endogenous serine/threonine phosphatase prolong the duration of single NMDA channel openings, bursts, clusters and superclusters. Okadaic acid, a non-selective phosphatase inhibitor, prolongs channel openings only at a concentration that inhibits the Ca2+/calmodulin-dependent phosphatase 2B (calcineurin), and is ineffective when Ca2+ entry through NMDA channels is prevented. Furthermore, FK506, an inhibitor of calcineurin, mimics the effects of okadaic acid. Thus in adult neurons, calcineurin, activated by calcium entry through native NMDA channels, shortens the duration of channel openings. Simulated synaptic currents were enhanced after phosphatase inhibition, which is consistent with the importance of phosphorylation of the NMDA-receptor complex in the short- and long-term control of neuronal excitability.
...
PMID:Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. 751 73

Whole-cell recordings were made from dorsomedial nucleus tractus solitarii neurons in thin coronal medullary slices of the rat, at the level of the area postrema. Monosynaptic excitatory postsynaptic currents (EPSCs) were evoked in the tractus solitarius by electrical stimulation in the presence of D-2-amino-5-phosphonopentanoic acid (AP5) and bicuculline. Currents were also evoked by pressure ejection of (S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) in the presence of AP5, bicuculline, and tetrodotoxin or muscimol in the presence of 6,7-dinitroquinoxaline-2,3-dione and AP5. The metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate [(1S,3R)-ACPD] reversibly depressed the EPSC and muscimol currents and reversibly potentiated AMPA currents. The effects of (1S,3R)-ACPD were blocked in the presence of a low concentration of the phosphoprotein phosphatase (PP)1 and PP2A inhibitor okadaic acid (OA) but not by a low concentration of the PP inhibitor calyculin A. The immunosuppressant agent FK506 failed to block (1S,3R)-ACPD effects on AMPA currents. However, (1S,3R)-ACPD applied in the presence of FK506 produced a reversible potentiation of muscimol currents. We previously demonstrated that the cell-permeant cGMP analog 8-Br-cGMP can mimic many of the effects of (1S,3R)-ACPD. OA antagonized the effects of 8-Br-cGMP in the present investigation. Finally, we previously demonstrated that brief tetanic stimulation results in the activation of a presynaptic mGluR autoreceptor and depression of subsequently evoked EPSCs. OA similarly blocked tetanus-induced depression of EPSCs. These findings suggest that mGluRs on tractus solitarius afferents and first-order nucleus tractus solitarii neurons may modulate glutamate release and AMPA and gamma-aminobutyric acid type A receptor activity via activation of one or more PPs, such as PP2A and/or calcineurin.
...
PMID:Inhibition of phosphoprotein phosphatases blocks metabotropic glutamate receptor effects in the rat nucleus tractus solitarii. 751 97

In response to Ca2+ entry, several prominent brain nerve terminal phosphoproteins undergo dephosphorylation, but the relation between dephosphorylation and neurotransmitter release is unknown. Using the immunosuppressants cyclosporin A (CsA) and L-683,590 (FK-520) to inhibit specifically the Ca2+/calmodulin-dependent protein phosphatase calcineurin, we demonstrate here that Ca(2+)-dependent dephosphorylation in isolated rat brain nerve terminals (synaptosomes) is mediated by calcineurin. Pretreatment with micromolar CsA resulted in a 76-95% inhibition of stimulation-induced decreases in 32P-labeled dynamin (previously referred to as dephosphin), a phosphoprotein of M(r) = 145,000 (145-kDa protein), and a phosphoprotein of M(r) = 170,000 (170-kDa protein). Pretreatment with FK-520 also inhibited Ca(2+)-dependent dephosphorylation. Using hypotonic lysates of 32P-labeled synaptosomes, the addition of Ca2+ plus calmodulin, but not either agent alone, induced dynamin dephosphorylation. CsA and FK-520 had little to no effect on the release of glutamate induced by either K(+)-depolarization or the Ca2+ ionophore ionomycin. In contrast, calcineurin inhibition led to a substantial enhancement of glutamate release evoked by the K(+)-channel blocker 4-aminopyridine, an agent whose action most closely mimics physiological stimulation. Calcineurin inhibition had no effect on stimulation-induced changes in synaptosomal Ca2+ levels. Based on our findings, we hypothesize that Ca(2+)-dependent protein dephosphorylation resulting from calcineurin activation during physiological stimulation limits neurotransmitter release from brain nerve terminals, perhaps being dependent upon cyclic repolarization of the membrane during stimulation.
...
PMID:Calcineurin-mediated protein dephosphorylation in brain nerve terminals regulates the release of glutamate. 752 34

Synaptic plasticity is modulated by Ca(2+)-induced alterations in the balance between phosphorylation and dephosphorylation. Recent evidence suggests that calcineurin, the Ca(2+)-calmodulin-dependent phosphatase (2B), modulates the activity of postsynaptic glutamate receptors. However, in rat cortex, calcineurin is enriched mainly in presynaptic, not postsynaptic, fractions. To determine if calcineurin modulates glutamatergic neurotransmission through a presynaptic mechanism, we used whole-cell patch clamp experiments to test effects of two specific calcineurin inhibitors, cyclosporin A (CsA) and FK506, on synaptic activity in fetal rat cortical neurons. The rate of spontaneous action-potential firing was markedly increased by either CsA or FK506 but was unaffected by rapamycin, a structural analog of FK506 which has no effect on calcineurin. In voltage-clamp experiments, CsA increased the rate but not the amplitude of glutamate receptor-mediated, excitatory postsynaptic currents, suggesting an increased rate of glutamate release. CsA had no effect on the amplitude of currents evoked by brief bath application of selective glutamate receptor agonists, providing further evidence for a pre- rather than postsynaptic site of action. In conclusion, these data indicate that calcineurin modulates glutamatergic neurotransmission in rat cortical neurons through a presynaptic mechanism.
...
PMID:Presynaptic modulation of cortical synaptic activity by calcineurin. 754 35

Previous studies have shown that 4-aminopyridine (4AP) induced Ca-influx effects the release of glutamate from nerve terminals (synaptosomes) isolated from rat cerebral cortex. We now show that the Ca-dependent component of this release is potentiated by preincubation of the synaptosomes with the immunosuppressant, FK506, an inhibitor of protein phosphatase-2B (calcineurin). FK506 did not inhibit the Ca-independent release of glutamate from a cytosolic pool. Examination of the effect of FK506 on the influx of Ca elicited by 4AP indicated that inhibition of calcineurin activity resulted in an increase of voltage-dependent Ca-influx. Based on these results, we suggest that protein dephosphorylation effected by calcineurin may suppress voltage-dependent Ca-channel activity and in so doing inhibits evoked glutamate release. Activation of calcineurin produced by initial Ca-entry may represent a negative feedback to limit the activity of Ca-channels coupled to the release of glutamate.
...
PMID:A role for calcineurin (protein phosphatase-2B) in the regulation of glutamate release. 754 82

Alterations in situ in the phosphorylation state of the microtubule-associated protein tau were examined in response to increasing intracellular levels of Ca2+ through N-methyl-D-aspartate (NMDA)-receptor activation, or activating cyclic AMP (cAMP)-dependent protein kinase (cAMP-PK), in rat cerebral-cortical slices. Increasing intracellular concentrations of Ca2+ by treatment of the brain slices with the glutamate analogue NMDA in depolarizing conditions (55 mM KCl) resulted in dephosphorylation of tau. Addition of KCl+NMDA to the slices resulted in a 40% decrease in 32P incorporation into tau, whereas addition of KCl or NMDA alone had no effect on tau phosphorylation. The KCl+NMDA-induced dephosphorylation of tau was blocked by the non-competitive NMDA-receptor antagonist MK801. Determine the involvement of the Ca2+/calmodulin-dependent phosphatase, calcineurin, in the KCl+NMDA-induced dephosphorylation of tau, slices were pretreated with the calcineurin inhibitor Cyclosporin A. Pretreatment of the rat brain slices with Cyclosporin A completely abolished the dephosphorylation of tau induced by the addition of KCl+NMDA. The dephosphorylation of tau in situ was site-selective, as indicated by the loss of 32P label from only a few select peptides. Activation of cAMP-PK by stimulating adenylate cyclase in rat cerebral-cortical slices with forskolin resulted in a 73% increase over control levels in 32P incorporation into immunoprecipitated tau. Two-dimensional phosphopeptide mapping revealed that most of the sites on tau phosphorylated in brain slices in response to increased cAMP levels were the same as those phosphorylated on isolated tau by purified cAMP-PK. Although the state of tau phosphorylation is certainly regulated by many protein phosphatases and kinases in vivo, to our knowledge this study provides the first direct evidence of a specific protein phosphatase and kinase that modulate the phosphorylation state of tau in situ.
...
PMID:Modulation of the phosphorylation state of tau in situ: the roles of calcium and cyclic AMP. 761 80

1. In acutely isolated hippocampal cells, NMDA and glutamate application suppressed GABAA receptor-mediated responses. We studied the cellular events underlying the interaction between the two classes of receptors by using a whole-cell voltage-clamp approach. 2. Following an NMDA application, an outward current mediated by GABAA receptor activation (GABA response) was suppressed for up to 12 s. The suppression of the GABA response was reduced when Ca2+ in the extracellular solution was replaced by Ba2+ or when intracellular BAPTA (1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid) was increased from 1 to 10 mM. 3. Replacing ATP in the intracellular solution by adenosine-5'-O-3-thiotriphosphate reduced the suppressive effect of NMDA application on the GABA response. Okadaic acid, a phosphatase inhibitor, also prevented the NMDA-induced suppression of the GABA response. In addition, when the intracellular perfusing solution contained the calcineurin autoinhibitory fragment (50 microM), suppression of the GABA response by the NMDA current was also reduced. 4. Intracellular perfusion of an activated form of the Ca(2+)-dependent phosphatase, calcineurin, suppressed GABA responses. 5. The results show that NMDA responses elicited in hippocampal neurones transiently suppressed GABA responses. The data suggest that the functional linkage of the NMDA response with the GABA response was established via a Ca(2+)-dependent dephosphorylation process.
...
PMID:Suppression of GABAA receptor responses by NMDA application in hippocampal neurones acutely isolated from the adult guinea-pig. 771 26


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---