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)

Glutamate receptors responding to N-methyl-D: -aspartate (NMDA) are involved in neural development, excitotoxicity and neuronal plasticity. Each receptor includes at least two NR2 subunits. Here, we have examined the effects of selective antagonists of NR2A and NR2B subunits (NVP-AAM07 and Ro25-6981 respectively) on the effects of NMDA in the CA1 field of rat hippocampal slices. We have observed that Ro25-6981 potentiates, rather than blocks, the effects of NMD on field EPSPs and paired-pulse interactions (indicators of presynaptic effects) and on postsynaptic depolarisation in hippocampal slices. The NR2A subunit antagonist NVP-AAM077 blocks the effects of NMDA alone, or after potentiation by Ro25-6981. The potentiation of NMDA by Ro25-6981 was not prevented by staurosporine (protein kinase inhibitor), okadaic acid (an inhibitor of serine/threonine protein phosphatases) or anisomycin (protein synthesis inhibitor), but was prevented by cyclosporin A, which inhibits Ca2+/calmodulin-dependent phosphatase 2B [calcineurin]. NMDA-dependent long-term potentiation (LTP) induced by electrical stimulation was not prevented by Ro25-6981 but was prevented by selective blockade of the NR2A subunit. The results suggest that, at both presynaptic and postsynaptic sites in the rat hippocampus, NR2B-subunit-containing receptors limit NMDA receptor function by inhibitory restraint over NR2A-subunit-containing receptors, via calcineurin activation, and that LTP induction critically involves primarily receptors containing the NR2A subunit. Endogenous factors or drugs that modify this NR2B/NR2A interaction could have a major influence on synaptic transmission and plasticity in the brain.
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PMID:Selective subunit antagonists suggest an inhibitory relationship between NR2B and NR2A-subunit containing N-methyl-D: -aspartate receptors in hippocampal slices. 1558 Mar 38

We examined the effects of estradiol benzoate (E2) on the protein expression of calcineurin in amygdaloid and hippocampal structures of ovariectomized (OVX) rats. Significant decreases in levels of calcineurin immunolabeling were seen in the medial and basomedial, but not central or basolateral, amygdala. Estrogen also reduced calcineurin immunoreactivity in the CA1 region of the hippocampus, but not in the CA3 region, hilus or ventral or dorsal dentate gyrus structures of hippocampus. These results indicate that E2 acts on calcineurin in a neuroanatomically specific manner and may be involved in estrogen-mediated regulation of gene expression.
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PMID:Estrogen decreases levels of calcineurin in rat amygdala and hippocampus. 1564 Jul 71

Hypothyroidism impairs early long-term potentiation (LTP) in the CA1 but not in the dentate gyrus (DG) of hippocampus of anesthetized adult rats. Protein levels and activities of signaling molecules in both the CA1 and DG of surgically thyroidectomized and sham-operated euthyroid rats were measured. Basal levels of total calmodulin kinase II (CaMKII) protein in both the CA1 and DG were decreased in hypothyroidism. Marked reduction of basal P-CaMKII levels and CaMKII activity was seen in CA1, but not in the DG of the same hypothyroid animals. Basal levels of calmodulin and protein kinase Cgamma (PKCgamma) were decreased in CA1 but remained unchanged in the DG of hypothyroid rats. Basal calcineurin levels and activity, although enhanced in CA1, were reduced in the DG of hypothyroid rats. These findings suggest that the DG may possess a compensatory mechanism whereby calcineurin levels are reduced, to allow sufficient CaMKII activity to produce an apparently normal LTP in hypothyroid rats.
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PMID:Role of phosphorylated CaMKII and calcineurin in the differential effect of hypothyroidism on LTP of CA1 and dentate gyrus. 1571 6

Hypoxia is the most common cause of perinatal seizures and can be refractory to conventional anticonvulsant drugs, suggesting an age-specific form of epileptogenesis. A model of hypoxia-induced seizures in immature rats reveals that seizures result in immediate activation of the phosphatase calcineurin (CaN) in area CA1 of hippocampus. After seizures, CA1 pyramidal neurons exhibit a downregulation of GABA(A) receptor (GABA(A)R)-mediated inhibition that was reversed by CaN inhibitors. CaN activation appears to be dependent on seizure-induced activation of Ca2+-permeable AMPA receptors (AMPARs), because the upregulation of CaN activation and GABA(A)R inhibition were attenuated by GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] or Joro spider toxin. GABA(A)R beta2/3 subunit protein was dephosphorylated at 1 h after seizures, suggesting this subunit as a possible substrate of CaN in this model. Finally, in vivo administration of the CaN inhibitor FK-506 significantly suppressed hypoxic seizures, and posttreatment with NBQX (2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline) or FK-506 blocked the hypoxic seizure-induced increase in CaN expression. These data suggest that Ca2+-permeable AMPARs and CaN regulate inhibitory synaptic transmission in a novel plasticity pathway that may play a role in epileptogenesis in the immature brain.
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PMID:AMPA/kainate receptor-mediated downregulation of GABAergic synaptic transmission by calcineurin after seizures in the developing rat brain. 1637 59

Depotentiation, the reversal of long-term potentiation (LTP), can be induced by activation of metabotropic glutamate receptors (mGluRs) or NMDA receptors (NMDARs). Although NMDAR-dependent depotentiation is due to a protein phosphatase-dependent erasure of LTP, the notion that mGluR-dependent depotentiation also involves LTP erasure is controversial. To address this issue we used electrophysiological and biochemical approaches to investigate mGluR-dependent depotentiation in hippocampal slices. Activating group I mGluRs with (R,S)-3,5-dihydroxyphenylglycine (DHPG) induced robust depotentiation in both the CA1 and CA3 regions of hippocampal slices. Western immunoblotting of samples prepared from DHPG-treated slices revealed, however, that activation of group I mGluRs causes a transient increase in phosphorylation of AMPA receptor GluR1 subunits at sites crucial for LTP and under some conditions causes persistent activation of alphaCamKII. The paradoxical ability of DHPG to induce depotentiation while at the same time activating signaling pathways involved in LTP suggests that LTP might not be erased by mGluR-dependent depotentiation. Consistent with this, DHPG-induced depotentiation did not restore the ability of high-frequency stimulation to induce LTP at synapses that had previously undergone saturating levels of LTP. In addition, blocking the expression of DHPG-induced LTD revealed hidden LTP at depotentiated synapses. Our results indicate that LTP and mGluR-dependent LTD can co-exist at excitatory synapses.
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PMID:Long-term potentiation persists in an occult state following mGluR-dependent depotentiation. 1585 20

We identified CAT 53 by cDNA hybridization selection as an expressed sequence tag (EST), located in the vicinity of HLA-C and designated as CAT (for HLA-C associated transcript) 53. CAT 53 encodes a protein described by others and commonly known as phosphatase 1 nuclear targeting subunit (PNUTS). PNUTS is a potent inhibitor of nuclear serine/threonine protein phosphatase 1 (PP1). We present the genomic organization of CAT 53, localize specific sites of mRNA transcription in thin sections of mouse brain by in-situ hybridization, and perform a structural analysis of the peptide domains. We also characterize the protein expression pattern for PNUTS by Western blotting and immunohistochemistry with PNUTS antibody in Alzheimer's disease (AD) brains and age-matched control brains. In-situ hybridization and immunohistochemistry analysis of human and mouse brain show high CAT 53 expression in the olfactory cortex, piriform cortex, and hippocampus. Very high expression of CAT 53 was found mainly in the hippocampus, frontal, and entorhinal cortex of control brains and in the neurofibrillary tangles of AD brain. In the hippocampus, CAT 53 is expressed in CA1 and CA3 cell layers and in the dentate gyrus. The hippocampus is known to play a fundamental role in learning and episodic memories and has been implicated in a number of neurological and psychiatric disorders, including AD, epilepsy, and schizophrenia. Our findings suggest that PNUTS, encoded by CAT 53 on 6p21.3, may have a role in the progression of AD.
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PMID:CAT 53: a protein phosphatase 1 nuclear targeting subunit encoded in the MHC Class I region strongly expressed in regions of the brain involved in memory, learning, and Alzheimer's disease. 1589 2

Calcineurin, a neuronally enriched, calcium-stimulated phosphatase, is an important modulator of many neuronal processes, including several that are physiologically related to the pathology of traumatic brain injury. The effect of moderate, central fluid percussion injury on the subcellular distribution of this important neuronal enzyme was examined. Animals were sacrificed at several time points post-injury and calcineurin distribution in subcellular fractions was assayed by Western blot analysis and immunohistochemistry. A persistent increase in calcineurin concentration was observed in crude synaptoplasmic membrane-containing fractions. In cortical fractions, calcineurin immunoreactivity remained persistently increased for 2 weeks post-injury. In hippocampal homogenates, calcineurin immunoreactivity remained increased for up to 4 weeks. Finally, immunohistochemical analysis of hippocampal slices revealed increased staining in the apical dendrites of CA1 neurons. The increased staining was greatest in magnitude 24 h post-injury; however, staining was still more intense than control 4 weeks post-injury. The data support the conclusion that fluid percussion injury results in redistribution of the enzyme in the rat forebrain. These changes have broad physiological implications, possibly resulting in altered cellular excitability or a greater likelihood of neuronal cell death.
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PMID:A persistent change in subcellular distribution of calcineurin following fluid percussion injury in the rat. 1591 62

Hypothyroidism impairs synaptic plasticity as well as learning and memory. Clinical reports are conflicting about the ability of thyroid hormone replacement therapy to fully restore the hypothyroidism-induced learning and memory impairment. Recently, we have shown that hypothyroidism impairs LTP and cognition in adult rats. We have studied the effect of thyroxin replacement therapy on hypothyroidism-induced LTP impairment using electrophysiological and molecular approaches. Recording from CA1 region of the hippocampus in anesthetized adult rat indicated that 6 weeks of thyroxin replacement therapy (20 microg/kg/day) fully restored LTP impaired by hypothyroidism. Western blotting showed reduction in phosphorylated (P)-CAMKII, total-CaMKII, neurogranin, and calmodulin basal levels in the CA1 region of the hippocampus of hypothyroid rats. The levels of these molecules were normalized by thyroxin replacement therapy. The hypothyroid-induced elevation of basal calcineurin levels and activity was also normalized by thyroxin treatment. However, thyroxin replacement therapy did not restore hypothyroidism-induced reduction in PKCgamma basal protein levels. Additionally, real-time PCR, showed a reduction in basal neurogranin mRNA level that was normalized by thyroxin replacement therapy. In the sham (control) rats, induction of LTP by high-frequency stimulation increases P-CaMKII, and total CaMKII levels as well as CaMKII phosphotransferase activity. However, in hypothyroid rats, the same stimulation protocol induced an increase only in total-CaMKII. Thyroxin treatment normalized the levels and activity of these molecules. The results demonstrated that thyroxin therapy normalized the electrophysiological and molecular effects of hypothyroidism on the CA1 region and emphasized the critical role P-CaMKII plays in hypothyroidism-induced LTP impairment.
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PMID:Levothyroxin restores hypothyroidism-induced impairment of LTP of hippocampal CA1: electrophysiological and molecular studies. 1600 82

Hypoxia is a common environmental stress that influences signaling pathways and cell function. Previous studies from our laboratory have identified significant differences in cellular responses to sustained or intermittent hypoxia with the latter proving more cytotoxic. We hypothesized that differences in susceptibility of neurons to intermittent (IH) and sustained hypoxia (SH) are mediated by altered Akt signaling. SH, but not IH, induced a significant increase in Akt activation in rat CA1 hippocampal region extracts compared with room air controls. Akt immunoprecipitations followed by proteomic analysis identified valosin-containing protein (VCP) as an Akt-binding protein. In addition, VCP expression and association with Akt was enhanced during SH, and this association was decreased upon phosphoinositide 3-kinase/Akt pathway blockade with LY294002. Active recombinant Akt phosphorylated recombinant VCP in vitro. Site-directed mutagenesis studies identified Ser352, Ser746, and Ser748 as Akt phosphorylation sites on VCP. In addition, rat CA1 hippocampal tissue exposed to SH exhibited an acidic pI shift of VCP. Protein phosphatase 2A treatment inhibited this acidic shift consistent with SH-induced phosphorylation of VCP in vivo. PC-12 cells transfected with active Akt, but not dominant negative Akt or vector, induced VCP expression and an acidic shift in VCP pI, which was inhibited by protein phosphatase 2A treatment. Furthermore, VCP association with ubiquitinated proteins was demonstrated in vector-transfected PC-12 cell lysates, whereas active Akt-transfected cells demonstrated a marked decrease in association of VCP with ubiquitinated proteins. We concluded that Akt phosphorylates VCP in vitro and in vivo, and VCP phosphorylation releases it from ubiquitinated substrate protein(s) possibly allowing ubiquitinated protein(s) to be degraded by the proteosome.
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PMID:Akt-mediated valosin-containing protein 97 phosphorylation regulates its association with ubiquitinated proteins. 1602 65

Diverse subtypes of nicotinic acetylcholine receptors (nAChRs), including fast-desensitizing alpha7-containing receptors, are expressed in the CNS. While nAChRs appear to regulate cognitive processing and synaptic plasticity, little is known to date about how this regulation occurs, particularly in brain regions known to be important for cognition. By combining patch-clamp electrophysiology with local photolysis of caged carbachol to rapidly activate the alpha7-containing nAChRs in rat hippocampal CA1 stratum radiatum interneurones in slices, we describe a novel transient up-regulation of channel function. The nAChRs were activated using a paired-pulse uncaging protocol, where the duration of the UV laser pulses (5-25 ms) and the interval between pulses (200 ms to 30 s) were varied. At relatively long interpulse intervals, we observed a strong (> 75%) decrease in the amplitude of the second response due to desensitization. However, when two pulses were applied at a 200 ms interval, a > 3-fold increase in the amplitude of the second response was observed, a phenomenon referred to here as paired-pulse potentiation. Interestingly, this potentiation appeared to be regulated by [Ca2+]i, and/or Ca2+-dependent processes, as it was significantly enhanced by dialysing cells with either the Ca2+ chelator BAPTA, or with peptide inhibitors of either calcineurin or PKC, and was attenuated by dialysing cells with the CaMKII inhibitor KN-93. No potentiation was observed using caged GABA or glutamate, indicating some specificity for nAChRs. Thus, rat hippocampal alpha7-containing nAChRs possess a newly described phenomenon of paired-pulse potentiation that may be involved in regulating synaptic plasticity in the hippocampus.
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PMID:Paired-pulse potentiation of alpha7-containing nAChRs in rat hippocampal CA1 stratum radiatum interneurones. 1614 Dec 65


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