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)

Long-term desensitization of the AMPA-selective glutamate receptors in Purkinje cells was examined in rat cerebellar slices by means of the wedge recording method. It was not induced by application of AMPA alone, but occurred regularly when slices were conditioned by perfusion with 0.5 mM 8-bromo-cGMP (but not cAMP derivatives) or the protein phosphatase inhibitors, okadaic acid and calyculin A. Phorbol esters also showed a similar effect. The 8-bromo-cGMP desensitization was antagonized by KT5823, an inhibitor of protein kinase G, while the effect of calyculin A was inhibited by polymyxin B, H-7, or K252a. These results suggest that AMPA receptors are persistently desensitized due to concerted action of both an agonist and an enzymatic system involving protein kinases G and C and a protein phosphatase inhibitor.
...
PMID:Protein kinases and phosphatase inhibitors mediating long-term desensitization of glutamate receptors in cerebellar Purkinje cells. 132 54

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.
...
PMID:A role for protein kinases and phosphatases in the Ca(2+)-induced enhancement of hippocampal AMPA receptor-mediated synaptic responses. 791 94

During opiate withdrawal, there is an elevated and prolonged efflux of glutamate and aspartate in the locus coeruleus (LC). The enhanced excitatory amino acid (EAA) release is thought to contribute to the withdrawal-induced activation of LC neurons and to the expression of the physical withdrawal syndrome. In this study, prolonged bath applications of glutamate to LC neurons in brain slices resulted in a slowly developing long-term glutamate desensitization (LTGD). LTGD was observed during extracellular recordings or in neurons voltage-clamped to -60mV, in both cases reaching a maximum of about a 50% reduction in the glutamate response. Responses in the desensitized cells gradually recovered within 3 h. Cyclothiazide, an inhibitor of rapid glutamate receptor desensitization did not prevent LTGD. LTGD could not be induced by prolonged applications of EAA agonists other than glutamate, either alone or in various combinations. However, after induction by glutamate, there was cross-desensitization to quisqualate but not to AMPA or NMDA. LTGD was blocked by either lowering extracellular Ca2+ concentrations or by treatment with the protein kinase C inhibitor chelerythrine but not by inhibitors of calcium/calmodulin-dependent kinase or nitric oxide synthase. Applications of the protein kinase C activator phorbol diacetate did not cause a decrease in glutamate responses indicating that an activation of protein kinase C may not be sufficient for desensitization to occur. A decrement of the glutamate response resembling LTGD occurred after treatment by the protein phosphatase inhibitors okadaic acid or calyculin A. LC neurons in brain slices prepared from opiate-withdrawn rats exhibited glutamate responses that were initially desensitized and recovered within 3 h after withdrawal. These results suggest that LTGD in LC neurons may occur during opiate withdrawal and could contribute to the time course of LC hyperactivity and the associated behavioral withdrawal syndrome.
...
PMID:Long-term glutamate desensitization in locus coeruleus neurons and its role in opiate withdrawal. 852 94

Hypothetical mechanism of homo-, hetero-, and associative LTD in the efficacy of excitatory synaptic transmission is suggested. According to this hypothesis, the same mechanisms underlie these effects. It is proposed that the following conditions are necessary and sufficient to produce different types of LTD. Conditioning and test stimuli must activate the common inhibitory neuron which is presynaptic to the target cell. The postsynaptic Ca2+ concentration which is regulated by metabotropic mGlu and GABAb receptor activation and opening of voltage-dependent Ca2+ channels must exceed a certain moderate level. This leads to an increase in protein phosphatase and decrease in protein kinases concentrations and cause dephosphorylation of ionotropic AMPA, NMDA, and GABAa receptors. Dephosphorylation results in a decrease of the sensitivity of excitatory and increase in the sensitivity of inhibitory receptors and causes simultaneous LTD excitatory and LTP of inhibitory synaptic transmission.
...
PMID:[The simultaneous activation of excitatory and inhibitory inputs as a condition for the induction of homo-, hetero- and associative long-term excitation depression]. 858 5

We proposed that acute ammonia toxicity is mediated by activation of NMDA receptors. To confirm this hypothesis we have tested whether different NMDA receptor antagonists, acting on different sites of NMDA receptors, prevent death of mice induced by injection of 14 mmol/Kg of ammonium acetate, a dose that induces death of 95% of mice. MK-801, phencyclidine and ketamine, which block the ion channel of NMDA receptors, prevent death of at least 75% of mice. CPP, AP-5, CGS 19755, and CGP 40116, competitive antagonists acting on the binding site for NMDA, also prevent death of at least 75% of mice. Butanol, ethanol and methanol which block NMDA receptors, also prevent death of mice. There is an excellent correlation between the EC50 for preventing ammonia-induced death and the IC50 for inhibiting NMDA-induced currents. Acute ammonia toxicity is not prevented by antagonists of kainate/AMPA receptors, of muscarinic or nicotinic acetylcholine receptors or of GABA receptors. Inhibitors of nitric oxide synthase afford partial protection against ammonia toxicity while inhibitors of calcineurin, of glutamine synthetase or antioxidants did not prevent ammonia-induced death of mice. These results strongly support the idea that acute ammonia toxicity is mediated by activation of NMDA receptors.
...
PMID:NMDA receptor antagonists prevent acute ammonia toxicity in mice. 892 86

The cellular mechanisms underlying the neuroprotective action of the immunosuppressant FK506 in experimental stroke remain uncertain, although in vitro studies have implicated an antiexcitotoxic action involving nitric oxide and calcineurin. The present in vivo study demonstrates that intraperitoneal pretreatment with 1 and 10 mg/kg FK506, doses that reduced the volume of ischemic cortical damage by 56-58%, did not decrease excitotoxic damage induced by quinolinate, NMDA, and AMPA. Similarly, intravenous FK506 did not reduce the volume of striatal quinolinate lesions at a dose (1 mg/kg) that decreased ischemic cortical damage by 63%. The temporal window for FK506 neuroprotection was defined in studies demonstrating efficacy using intravenous administration at 120 min, but not 180 min, after middle cerebral artery occlusion. The noncompetitive NMDA receptor antagonist MK801 reduced both ischemic and excitotoxic damage. Histopathological data concerning striatal quinolinate lesions were replicated in neurochemical experiments. MK801, but not FK506, attenuated the loss of glutamate decarboxylase and choline acetyltransferase activity induced by intrastriatal injection of quinolinate. The contrasting efficacy of FK506 in ischemic and excitotoxic lesion models cannot be explained by drug pharmacokinetics, because brain FK506 content rose rapidly using both treatment protocols and was sustained at a neuroprotective level for 3 d. Although these data indicate that an antiexcitotoxic mechanism is unlikely to mediate the neuroprotective action of FK506 in focal cerebral ischemia, the finding that intravenous cyclosporin A (20 mg/kg) reduced ischemic cortical damage is consistent with the proposed role of calcineurin.
...
PMID:Neuroprotective actions of FK506 in experimental stroke: in vivo evidence against an antiexcitotoxic mechanism. 927 29

We recently discovered that CO2/H+-sensitive neurons in the ventral medullary surface (VMS) are immunoreactive to glutamate, glutamic acid decarboxylase (GAD), calcineurin and cAMP. We then tested the hypothesis that glutamate, GABA, calcineurin and cAMP affect the activity of CO2/H+-sensitive neurons in the VMS. Using male Wistar rats anesthetized with urethane and pentobarbital, we checked for changes in relative tidal volume (VT) and respiratory frequency (f) in response to injecting the VMS with a variety of test agents dissolved in mock CSF. Respiratory changes occurred immediately and were dose-dependent. (1) 200-1600 pmol Glutamate increased VT but decreased f. The glutamate effect was never abolished by concomitant injection of AP5, a NMDA receptor antagonist, but was abolished by CNQX, an AMPA receptor antagonist, indicating predominance of AMPA receptors in the CO2/H+-sensitive neurons in the VMS. (2) 200-1600 pmol GABA decreased both VT and f. The GABA effect was never abolished by concomitant injection of saclofen, a GABA(B) receptor antagonist, but was abolished by bicuculline, a GABA(A) receptor antagonist, indicating predominance of GABA(A) receptors in the CO2/H+-sensitive neurons in the VMS. (3) 4-32 microg Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase 2B, and 200-1600 pmol FK506, selective inhibitor of calcineurin, had no effect on respiration when they were applied extracellularly, but 400-3200 pmol BAPTA-AM, an intracellular Ca2+-chelating agent, decreased both VT and f, indicating involvement of intracellular Ca2+ in the excitatory mechanisms of respiration. (4) 100-800 pmol IBMX, an enhancer of intracellular cAMP, decreased both VT and f, indicating involvement of cAMP in the inhibitory mechanisms of respiration. These results indicate that the CO2/H+-sensitive neurons in the VMS contain glutamate and/or GABA in cytoplasma, possess AMPA and/or GABA(A) receptors on surface of plasma membrane, and compose the internal circuit, and that their activities are regulated by Ca2+ and cAMP.
...
PMID:Pharmacological properties of the CO2/H+-sensitive area in the ventral medullary surface assessed by the effects of chemical stimulation on respiration. 976 77

Neuronal degeneration and cell death can result from excessive activation of receptors for the excitatory neurotransmitter glutamate; however, the very earliest changes in cytoskeletal organization have not been well documented. We have used an in vitro model system to examine the early consequences of intense glutamate receptor activation on dendritic spine synapses. Cultured hippocampal neurons exposed to NMDA for as little as 5 min exhibited a rapid and extensive loss of dendritic spines. Staining for the presynaptic marker synapsin 1 and the postsynaptic density proteins PSD-95 and the NR1 subunit of NMDA receptors remained intact. The disappearance of spines was accompanied by a selective loss of filamentous actin staining at synapses. The NMDA-induced loss of spine actin was time- and concentration-dependent and blocked by NMDA receptor antagonists. The effect was mimicked by L-glutamate, AMPA, and ionomycin but not by agonists of L-type calcium channels or of metabotropic glutamate receptors. The effect of NMDA on local actin assembly was strongly attenuated by pretreatment with an actin stabilizing compound or by an antagonist of the calcium-dependent protein phosphatase calcineurin. Immunoreactivity for calcineurin was enriched at synapses together with F-actin. These results indicate that the actin-mediated stability of synaptic structure is disrupted by intense glutamate receptor activity and that calcineurin blockers may be useful in preventing such destabilization.
...
PMID:Regulation of F-actin stability in dendritic spines by glutamate receptors and calcineurin. 982 42

1. In acutely isolated rat sacral dorsal commisural nucleus (SDCN) neurones, application of kainate (KA) reversibly potentiated glycine-evoked Cl- currents (IGly) in a concentration-dependent manner. 2. The cellular events underlying the interaction between non-NMDA receptors and glycine receptors were studied by using nystatin-perforated patch and cell-attached single-channel recording modes. 3. The action of KA was not accompanied by a shift in the reversal potential for IGly. In dose-response curves, KA potentiated IGly without significantly changing glycine binding affinity. 4. GYKI 52466 blocked while NS-102 had no effect on the KA-induced potentiation of IGly. 5. The potentiation was reduced when KA was applied in a Ca2+-free extracellular solution or in the presence of BAPTA AM, and was independent of the activation of voltage-dependent Ca2+ channels. 6. Pretreatment with KN-62, a selective Ca2+-calmodulin-dependent protein kinase II (CaMKII) inhibitor, abolished the action of KA. Inhibition of calcineurin converted the KA-induced potentiation to a sustained one. 7. Single-channel recordings revealed that KA decreased the mean closing time of glycine-gated single-channel activity, resulting in an increase in the probability of channel opening. 8. It is proposed that Ca2+ entry through AMPA receptors modulates the glycine receptor function via coactivation of CaMKII and calcineurin in SDCN neurones. This interaction may provide a new postsynaptic mechanism for control of inhibitory synaptic signalling and represent one of the important regulatory mechanisms of spinal nociception.
...
PMID:Modulation of the glycine response by Ca2+-permeable AMPA receptors in rat spinal neurones. 988 41

Modulation of AMPA-type glutamate channels is important for synaptic plasticity. Here we provide physiological evidence that the activity of AMPA channels is regulated by protein phosphatase 1 (PP-1) in neostriatal neurons and identify two distinct molecular mechanisms of this regulation. One mechanism involves control of PP-1 catalytic activity by DARPP-32, a dopamine- and cAMP-regulated phosphoprotein highly enriched in neostriatum. The other involves binding of PP-1 to spinophilin, a protein that colocalizes PP-1 with AMPA receptors in postsynaptic densities. The results suggest that regulation of anchored PP-1 is important for AMPA-receptor-mediated synaptic transmission and plasticity.
...
PMID:Protein phosphatase 1 modulation of neostriatal AMPA channels: regulation by DARPP-32 and spinophilin. 1019 74


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

---