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)

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.
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PMID:Inhibition of phosphoprotein phosphatases blocks metabotropic glutamate receptor effects in the rat nucleus tractus solitarii. 751 97

A role of Ca2+/calmodulin-dependent protein phosphatase (calcineurin) in induction of long-term potentiation (LTP) was investigated using its selective inhibitor, FK506, in visual cortical slices of young rats. Field potentials or excitatory postsynaptic potentials (EPSPs) to test stimulation of white matter were recorded extra- or intracellularly from layer 2/3, and tetanic stimulation (tetanus) was applied to the white matter at 5 Hz. During the application of FK506 (1 microM), short tetanus (6 s) which had rarely induced LTP in the normal medium, became effective in inducing LTP. Tetanus for 1 min in the presence of FK506 induced LTP with higher probability than in the normal medium. To test possible involvement of presynaptic mechanisms, paired pulses at 50 ms intervals were given to the white matter. The facilitation ratio of the second to first EPSPs was not significantly changed by FK506 and after the induction of LTP, suggesting that the action of FK506 may not be presynaptic. To confirm this, FK506 was injected directly into neurons through recording electrodes. In cases in which stable EPSPs were recorded, the probability of LTP induction became higher than that obtained with normal electrodes. These results suggest that calcineurin plays a role in processes antagonizing the induction of LTP in visual cortex.
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PMID:Effects of an inhibitor for calcium/calmodulin-dependent protein phosphatase, calcineurin, on induction of long-term potentiation in rat visual cortex. 752 Jan 43

Long-term potentiation (LTP) and long-term depression (LTD) are calcium-dependent forms of synaptic plasticity observed in area CA1 of the hippocampus. Low-frequency tetani (1-5 Hz) activates protein phosphatases to induce LTD, whereas high-frequency tetani (> 25 Hz) activates protein kinases to induce LTP. A tetanus at an intermediate frequency (10 Hz), however, does not result in a change in synaptic efficacy [Dudek and Bear, (1992), Proc. Natl. Acad. Sci. USA, 89:4363-4367]. We hypothesized that the 10-Hz tetanus results in no long-term change in synaptic efficacy due to a balance of the activity of protein phosphatases and protein kinases. We manipulated protein kinase/phosphatase activity at a 10-Hz tetanus to test this hypothesis. A 10-Hz tetanus under normal conditions results in a transient depression which returns to baseline in 25 min. However, inhibiting kinase activity with the protein kinase inhibitor H-7, or decreasing extracellular calcium concentration, results in the 10-Hz tetanus, inducing LTD. Conversely, inhibiting phosphatase activity with the protein phosphatase inhibitor tautomycin, or increasing extracellular calcium concentration, results in the 10-Hz tetanus, inducing LTP. These results suggest that the relative balance of protein kinase and phosphatase activity (and/or the calcium levels activating them) determines the expression of specific forms of synaptic plasticity, and that these forms lie on a continuum.
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PMID:Protein kinase and phosphatase activity regulate the form of synaptic plasticity expressed. 889 Apr 51

Protein phosphorylation and dephosphorylation are believed to functionally couple neuronal activity and synaptic plasticity. Our previous results indicated that postsynaptic Ca2+/calmodulin (CaM) signaling pathways play an important role in setting synaptic strength, and calcineurin (CaN) activity limits synaptic responses during basal synaptic transmission and long-term potentiation expression. The inhibition of postsynaptic CaN activity by FK-506 or an autoinhibitory peptide induced synaptic potentiation in hippocampal slices, which occludes tetanus-induced LTP. FK-506-induced synaptic potentiation was expressed in adult but not young rats. To elucidate mechanisms underlying CaN-inhibited synaptic potentiation, we co-injected certain agents affecting Ca2+ signaling pathways with CaN inhibitors into CA1 neurons. Synaptic potentiation induced by FK-506 was significantly attenuated by co-injecting BAPTA, heparin/dantrolene (inhibitors of intracellular Ca2+ release), a CaM-binding peptide, or CaM-KII/PKC pseudosubstrate peptides. These results indicate that postsynaptic CaN activity can downregulate evoked synaptic transmission by weakening intracellular Ca2+ signals and downstream protein kinase activities.
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PMID:Postsynaptic calcineurin activity downregulates synaptic transmission by weakening intracellular Ca2+ signaling mechanisms in hippocampal CA1 neurons. 916 21

Attenuation of paired-pulse facilitation associated with synaptic potentiation mediated by postsynaptic mechanisms. J. Neurophysiol. 78: 2707-2716, 1997. The relationship between paired-pulse facilitation (PPF) and synaptic potentiation induced by various protocols and their cellular and molecular mechanisms were examined by extracellular field potential and current- or voltage-clamp recordings at CA1 synapses in rat hippocampal slices. Microelectrodes were used for both intracellular recordings and injections of modulators of calcium (Ca2+) and Ca2+/calmodulin (CaM) signaling pathways into postsynaptic neurons. Basal synaptic transmission was not accompanied by changes in PPF. Tetanic stimulation induced long-term potentiation (LTP) of synaptic transmission and attenuated PPF. Experiments stimulating two independent Schaffer collateral/commisural(S/C) pathways showed that PPF attenuation and tetanus-LTP were pathway specific. Postsynaptic injections of pseudosubstrate inhibitors of CaM-dependent protein kinase II and protein kinase C (CaM-KII/PKC), [Ala286]CaMKII286-302 plus PKC19-31, almost completely attenuated tetanus-LTP and reversed PPF attenuation but did not affect synaptic transmission and PPF under basal conditions. Postsynaptic injections of heparin and dantrolene (inhibitors of IP3 and ryanodine receptors at intracellular Ca2+ stores) prevented tetanus-LTP induction and PPF attenuation. Postsynaptic injections of calcineurin (CaN) inhibitors, CaN autoinhibitory peptide (CaN-AIP) or FK-506, enhanced synaptic transmission and decreased PPF. CaN-inhibited synaptic potentiation and PPF attenuation were unaffected by (-)-a-Amino-5-phosphonopentanoic, but blocked by coinjecting 1, 2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, heparin plus dantrolene, calmodulin-binding peptide, or [Ala286]CaMKII281-302 plus PKC19-31. PPF attenuation associated with tetanus-LTP or CaN-inhibited synaptic potentiation resulted from smaller increases in the potentiation of the second synaptic responses (R2) compared with the potentiation of the first responses (R1). Our results indicate that PPF attenuation is associated with synaptic potentiation mediated by postsynaptic mechanisms, and postsynaptic Ca2+/CaM signaling pathways play a dual role in synaptic plasticity. CaN activity limits synaptic transmission under basal conditions, whereas the activation of Ca2+-dependent protein kinases enhances synaptic transmission and attenuates PPF at central synapses.
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PMID:Attenuation of paired-pulse facilitation associated with synaptic potentiation mediated by postsynaptic mechanisms. 935 20

Amphiphysin I is an abundant presynaptic protein that interacts via its COOH-terminal src homology 3 (SH3) domain with the GTPase dynamin I and the inositol-5-phosphatase synaptojanin. Both dynamin I and synaptojanin I have a putative role in synaptic vesicle recycling and undergo rapid dephosphorylation in rat brain synaptosomes stimulated to secrete by a depolarizing stimulus. We show here that amphiphysin I also undergoes constitutive phosphorylation and stimulationdependent dephosphorylation. Dephosphorylation of amphiphysin I requires extracellular Ca2+ and is unaffected by pretreatment of synaptosomes with tetanus toxin. Thus, Ca2+ influx, but not synaptic vesicle exocytosis, is required for dephosphorylation. Dephosphorylation of amphiphysin I, like dephosphorylation of dynamin I and synaptojanin I, is inhibited by cyclosporin A and FK-506 (0.5 microM), two drugs that specifically block the Ca2+/calmodulin-dependent phosphatase 2B calcineurin, but not by okadaic acid (1 microM), which blocks protein phosphatases 1 and 2B. We also show by immunogold electron microscopy immunocytochemistry that amphiphysin I is localized in the nerve terminal cytomatrix and is partially associated with endocytic intermediates. These include the clathrin-coated buds and dynamin-coated tubules, which accumulate in nerve terminal membranes incubated in the presence of guanosine 5'-3-O-(thio)triphosphate. These data support the hypothesis that amphiphysin I, dynamin I, and synaptojanin I are physiological partners in some step(s) of synaptic vesicle endocytosis. We hypothesize that the parallel Ca2+-dependent calcineurin-dependent dephosphorylation of amphiphysin I and of its two major binding proteins is part of a process that primes the nerve terminal for endocytosis in response to a burst of exocytosis.
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PMID:Amphiphysin I is associated with coated endocytic intermediates and undergoes stimulation-dependent dephosphorylation in nerve terminals. 938 46

The effects of FK506, an immunosuppressant and protein phosphatase 2B (calcineurin) inhibitor, on the voltage-gated calcium channel (VGCC)-dependent long-term potentiation (LTP) were investigated in the CA1 region of mice hippocampal slices. VGCC-dependent LTP was induced either by a brief application of a potassium channel blocker tetraethyleneanmonium (TEA), or by a strong tetanic stimulation under the blockade of NMDA-receptors. FK506 (1-50 microM) produced dose-dependent inhibition on TEA-induced LTP. Cyclosporin A (CysA 50 microM), another calcineurin inhibitor, showed a similar inhibitory effect on TEA-induced LTP. FK506 (10 microM) also blocked the strong tetanus-induced LTP, but had no effect on the post-tetanic potentiation. By using a subthreshold weak tetanic stimulation protocol, we also found that low concentration of FK506 (1 microM) produced neither inhibition nor potentiation on VGCC-dependent LTP. These results showed FK506 and CysA exerted inhibitory effects on VGCC-dependent LTP, and suggest that calcineurin is involved in the processes of this kind of synaptic plasticity.
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PMID:A calcineurin inhibitor, FK506, blocks voltage-gated calcium channel-dependent LTP in the hippocampus. 967 35

Cyclosporine, a calcineurin inhibitor, significantly enhances spontaneous acetylcholine release after a brief tetanus and potentiates the effect of phorbol 12,13-dibutyrate. Both actions are prevented by the protein kinase C inhibitor, bisindolylmaleimide iodide. Protein kinase C and calcineurin thus play important roles in the balance between phosphorylation and dephosphorylation regulating spontaneous transmitter release at motor nerve terminals.
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PMID:Enhanced spontaneous transmitter release at murine motor nerve terminals with cyclosporine. 1019 10

Coincident pre- and postsynaptic activity generates long-term potentiation (LTP), a possible cellular model of learning and memory. LTP has two components: (1) an increase in the excitatory postsynaptic potential (EPSP), and (2) an increase in the ability of the EPSP to generate a spike (E-S coupling of LTP). We have used pharmacological and genetic approaches to address the molecular nature of E-S coupling in CA1 pyramidal neurons. Blockade of the Ca2+-sensitive phosphatase, calcineurin, prevents induction of E-S coupling without interfering with LTP of the EPSP. Calcineurin produces its effect on E-S coupling by inducing a long-lasting depression (LTD) of the GABA(A)-mediated inhibitory postsynaptic potentials (IPSPs). This LTD of the IPSP was prevented by blockade of NMDA receptors. Thus, the tetanus that elicits NMDA-dependent LTP mediates a coordinately regulated double function. It produces LTP of the EPSP and, concomitantly, LTD of the IPSP that leads to enhancement of E-S coupling.
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PMID:Calcineurin-mediated LTD of GABAergic inhibition underlies the increased excitability of CA1 neurons associated with LTP. 1079 4

We have used differential display to profile and compare the mRNAs expressed in the hippocampus of freely moving animals after the induction of long-term potentiation (LTP) at the perforant path-dentate gyrus synapse with control rats receiving low-frequency stimulation. We have combined this with in situ hybridization and have identified A-kinase anchoring protein of 150 kDa (AKAP-150) as a gene selectively up-regulated during the maintenance phase of LTP. AKAP-150 mRNA has a biphasic modulation in the dentate gyrus following the induction of LTP. The expression of AKAP-150 was 29% lower than stimulated controls 1 h after the induction of LTP. Its expression was enhanced 3 (50%), 6 (239%) and 12 h (210%) after induction, returning to control levels by 24 h postinduction. The NMDA receptor antagonist CPP blocked the tetanus-induced modulation of AKAP-150 expression. Interestingly, strong generalized stimulation produced by electroconvulsive shock did not increase the expression of AKAP-150. This implies that the AKAP-150 harbours a novel property of selective responsiveness to the stimulation patterns that trigger NMDA-dependent LTP in vivo. Its selective up-regulation during LTP and its identified functions as a scaffold for protein kinase A, protein kinase C, calmodulin, calcineurin and ionotropic glutamate receptors suggest that AKAP-150 encodes is an important effector protein in the expression of late LTP.
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PMID:LTP but not seizure is associated with up-regulation of AKAP-150. 1254 70


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