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)

Calcineurin, protein phosphatase 2B, is a calcium-binding protein that has been shown to modulate NMDA receptor activity (Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 369 (1994) 235; Regulation of glycine-insensitive desensitisation of the NMDA receptor in outside-out patches. J. Neurophysiol. 71 (1994) 754; Calcineurin acts via the C-terminus of NR2A to modulate desensitization of NMDA receptors. Neuropharmacology 42 (2002) 593) and synaptic transmission (Synaptic desensitization of NMDA receptors by calcineurin. Science 267 (1995) 1510; beta-adrenergic regulation of synaptic NMDA receptors by cAMP-dependent protein kinase. Neuron 16 (1996) 415). Calmodulin, a necessary co-factor for calcineurin (Calmodulin binding by calcineurin. J. Biol. Chem. 262 (1987) 15062), has also been shown to inhibit NMDA receptor activity (Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84 (1996) 745; Direct effects of calmodulin on NMDA receptor single-channel gating in rat hippocampal granule cells. J. Neurosci. 22 (2002) 8860) in a calcium dependent manner (Calmodulin mediates calcium-dependent inactivation of N-methyl-d-aspartate receptors. Neuron 21 (1998) 443; Interactions of calmodulin and alpha-actinin with the NR1 subunit modulate calcium-dependent inactivation of NMDA receptors. J. Neurosci. 19 (1999) 1165). In order to gain insight into the likely actions and interactions of calcineurin and calmodulin at excitatory synapses, we have investigated the effects of these two proteins on single NMDA receptor channel activity. Calcineurin and calmodulin are both known to reduce channel open time (Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 369 (1994) 235; Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84 (1996) 745), and the duration of receptor activations or superclusters. They are, therefore, predicted to shorten the synaptic current decay (Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 369 (1994) 235; Direct effects of calmodulin on NMDA receptor single-channel gating in rat hippocampal granule cells. J. Neurosci. 22 (2002) 8860). In agreement with Lieberman and Mody (Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 369 (1994) 235), the results of this study indicate calcineurin plus calmodulin reduces channel open time. However, this effect is not as pronounced as that observed in the presence of calmodulin alone. Calcineurin plus calmodulin was also found to increase single channel shut time. We conclude that in addition to its direct effects on single channel activity, calcineurin regulates the effects of calmodulin on NMDA receptor activity.
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PMID:Inhibitory interactions of calcineurin (phosphatase 2B) and calmodulin on rat hippocampal NMDA receptors. 1538 Mar 69

The electrosensory lobes (ELLs) of mormyrid and gymnotid fish are useful sites for studying plasticity and descending control of sensory processing. This study used immunocytochemistry to examine the functional circuitry of the mormyrid ELL. We used antibodies against the following proteins and amino acids: the neurotransmitters glutamate and gamma-aminobutyric acid (GABA); the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD); GABA transporter 1; the anchoring protein for GABA and glycine receptors, gephyrin; the calcium binding proteins calbindin and calretinin; the NR1 subunit of the N-methyl-D-aspartate glutamate receptor; the metabotropic glutamate receptors mGluR1alpha, mGluR2/3, and mGluR5; and the intracellular signaling molecules calcineurin, calcium calmodulin kinase IIalpha (CAMKIIalpha) and the receptor for inositol triphosphate (IP3R1alpha). Selective staining allowed for identification of new cell types including a deep granular layer cell that relays sensory information from primary afferent fibers to higher order cells of ELLS. Selective staining also allowed for estimates of relative numbers of different cell types. Dendritic staining of Purkinje-like medium ganglion cells with antibodies against metabotropic glutamate receptors and calcineurin suggests hypotheses concerning mechanisms of the previously demonstrated synaptic plasticity in these cells. Finally, several cell types including the above-mentioned granular cells, thick-smooth dendrite cells, and large multipolar cells of the intermediate layer were present in the two zones of ELL that receive input from mormyromast electroreceptors but were absent in the zone of ELL that receives input from ampullary electroreceptors, indicating markedly different processing for these two types of input. J. Comp. Neurol. 483:124-142, 2005. (c) 2005 Wiley-Liss, Inc.
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PMID:Immunocytochemical identification of cell types in the mormyrid electrosensory lobe. 1567 92

This study investigated the role of protein phosphatase 2B (calcineurin) in regulating phosphorylation of N-methyl-D-aspartate receptor (NMDAR) NR1 subunits and other phosphoproteins in the rat striatum in vivo. In chronically cannulated rats, microinjection of the calcineurin selective inhibitor cyclosporin A increased phosphorylation of NMDAR NR1 subunits at serine 896 and serine 897 in the injected dorsal striatum. The increase in NMDAR NR1 phosphorylation was dose-dependent in a dose range surveyed (0.005, 0.05, and 0.5 nmol). Parallel with increased serine phosphorylation of NR1 subunits, cyclosporin A dose-dependently increased phosphorylation of a Ca2+-sensitive protein kinase, extracellular signal-regulated protein kinase 1/2 (ERK1/2), and a Ca2+/cAMP-sensitive transcription factor, cAMP response element-binding protein (CREB), in the dorsal striatum. Using an immediate early gene product Fos as a reporter of inducible gene expression, cyclosporin A was found to upregulate Fos expression in the dorsal striatum. These results indicate that calcineurin plays an important role in the tonic dephosphorylation of NMDAR NR1 subunits and other two key cytoplasmic and nuclear signaling proteins (ERK1/2 and CREB) in striatal neurons.
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PMID:Inhibition of protein phosphatase 2B upregulates serine phosphorylation of N-methyl-D-aspartate receptor NR1 subunits in striatal neurons in vivo. 1589 Apr 44

The present study investigates the role of serine/threonine protein phosphatase 2A (PP2A) in the modulation of the phosphorylation of the NR1 and NR2B subunits of NMDA receptors in the spinal cord of rats following intradermal injection of capsaicin. The effects of a specific inhibitor of PP2A, fostriecin, on the expression of NR1, phospho-NR1, NR2B, and phospho-NR2B subunits of the NMDA receptor in the spinal cord of rats following noxious stimulation were examined. After continually perfusing with ACSF or fostriecin (3 microM) through a previously implanted microdialysis fiber for 30 min, central sensitization was initiated by injection of capsaicin into the plantar surface of the left paw of rats. The spinal cord was removed at different time points (30, 60, 90, 120, 180 min) after intradermal injection of capsaicin. Western blots were performed to examine the expression of NMDA subunits in spinal cord tissue by using specific antibodies. We found that the upregulated phosphorylation of both NR1 and NR2B subunits induced by capsaicin injection was significantly potentiated by the PP2A inhibitor without affecting the NR1 and NR2B protein itself. These results suggest that PP2A may have a regulatory effect on central sensitization induced by noxious stimuli in the periphery by regulating the phosphorylation state of NMDA receptors.
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PMID:Protein phosphatase modulates the phosphorylation of spinal cord NMDA receptors in rats following intradermal injection of capsaicin. 1591 30

N-methyl-d-aspartate receptor (NMDAR) stimulation activates many downstream mechanisms involved in both cell survival and cell death. The manner in which the NMDAR regulates one of these pathways, the p38 mitogen-activated protein kinase (p38) pathway, is currently unknown. In the present study, we have defined a developmental-, concentration-, and time-dependent phosphorylation and subsequent dephosphorylation of p38. In cultured hippocampal neurons 7-8 days in vitro (DIV7-8), NMDAR stimulation leads to a concentration-dependent increase in p38 phosphorylation (phospho-p38). However, in more mature neurons (>DIV17) application of NMDA produces concentration-dependent effects, such that low concentrations result in sustained increases in phospho-p38 levels, and high concentrations dephosphorylate p38 within 5 min. Conantokin G, an antagonist of NR1/2A/2B and NR1/2B receptors, inhibits p38 phosphorylation, while NR1/2B-specific antagonists prevent the rapid dephosphorylation of p38 without affecting p38 activation. Furthermore, inhibition of calcineurin prevents the activation of p38, whereas inhibition of phosphoinositide 3-kinase (PI3K) prevents the rapid dephosphorylation of p38. Our results support the presence of subtype-dependent pathways regulating p38 activation and deactivation: one involves NR1/2A/2B receptors activating calcineurin and resulting in p38 phosphorylation, and the other utilizes NR1/2B receptors binding to and activating PI3K and leading to the dephosphorylation of p38 in a manner involving both NR1/2A/2B receptor activation and tyrosine phosphorylation of NR2B. The ability of NMDAR subtype-specific mechanisms to regulate p38 has implications for NMDAR-mediated synaptic plasticity, gene regulation, and excitotoxicity.
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PMID:N-methyl-D-aspartate receptor subtype mediated bidirectional control of p38 mitogen-activated protein kinase. 1596 99

Casein kinase 1 (CK1) is a highly conserved serine/threonine kinase, present in virtually all cell types, in which it phosphorylates a wide variety of substrates. So far, no role has been found for this ubiquitous protein kinase in the physiology of nerve cells. In the present study, we show that CK1 regulates fast synaptic transmission mediated by glutamate, the major excitatory neurotransmitter in the brain. Through the use of CK1 inhibitors, we present evidence that activation of CK1 decreases NMDA receptor activity in the striatum via a mechanism that involves activation by this kinase of protein phosphatase 1 and/or 2A and resultant increased dephosphorylation of NMDA receptors. Indeed, inhibition of CK1 increases NMDA-mediated EPSCs in medium spiny striatal neurons. This effect is associated with an increased phosphorylation of the NR1 and NR2B subunits of the NMDA receptor and is occluded by the phosphatase inhibitor okadaic acid. The mGluR1, but not mGluR5, subclass of metabotropic glutamate receptors uses CK1 to inhibit NMDA-mediated synaptic currents. These results provide the first evidence for a role of CK1 in the regulation of synaptic transmission in the brain.
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PMID:Physiological role for casein kinase 1 in glutamatergic synaptic transmission. 1601 21

Excitotoxic cell death (ECD) is characteristic of mammalian brain following min of anoxia, but is not observed in the western painted turtle following days to months without oxygen. A key event in ECD is a massive increase in intracellular Ca(2+) by over-stimulation of N-methyl-d-aspartate receptors (NMDARs). The turtle's anoxia tolerance may involve the prevention of ECD by attenuating NMDAR-induced Ca(2+) influx. The goal of this study was to determine if protein phosphatases (PPs) and intracellular calcium mediate reductions in turtle cortical neuron whole-cell NMDAR currents during anoxia, thereby preventing ECD. Whole-cell NMDAR currents did not change during 80 min of normoxia, but decreased 56% during 40 min of anoxia. Okadaic acid and calyculin A, inhibitors of serine/threonine PP1 and PP2A, potentiated NMDAR currents during normoxia and prevented anoxia-mediated attenuation of NMDAR currents. Decreases in NMDAR activity during anoxia were also abolished by inclusion of the Ca(2+) chelator -- BAPTA and the calmodulin inhibitor -- calmidazolium. However, cypermethrin, an inhibitor of the Ca(2+)/calmodulin-dependent PP2B (calcineurin), abolished the anoxic decrease in NMDAR activity at 20, but not 40 min suggesting that this phosphatase might play an early role in attenuating NMDAR activity during anoxia. Our results show that PPs, Ca(2+) and calmodulin play an important role in decreasing NMDAR activity during anoxia in the turtle cortex. We offer a novel mechanism describing this attenuation in which PP1 and 2A dephosphorylate the NMDAR (NR1 subunit) followed by calmodulin binding, a subsequent dissociation of alpha-actinin-2 from the NR1 subunit, and a decrease in NMDAR activity.
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PMID:Calcium and protein phosphatase 1/2A attenuate N-methyl-D-aspartate receptor activity in the anoxic turtle cortex. 1613 40

Acute 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") treatment induces learning deficits in different animal models. In a passive avoidance learning task in rats, previous studies suggested a role for Ca2+/calmodulin-dependent protein kinase II (CaMKII) and N-methyl-D-aspartate (NMDA) receptors in the acute learning impairment. As cognitive deficits by "ecstasy" in humans have been only reported in frequent recreational users, we examined whether a repeated MDMA treatment could induce in rats lasting molecular changes related to memory consolidation of passive avoidance. In rats with a pronounced 5-HT depletion by MDMA, the effect of another drug challenge was also examined. The surface expression in the hippocampus of NMDA receptor subunits, the scaffolding postsynaptic density protein PSD-95, phosphorylated CaMKII and protein phosphatase 1 (PP1) was measured. In rats repeatedly treated with MDMA (10 mg/kg) twice daily for 4 consecutive days, hippocampal 5-HT levels were markedly reduced 1 week later. At this time, neither learning performance was affected nor changes in membrane levels of NMDA receptor subunits, PSD-95, CaMKII and PP1 were found. In these rats, however, another drug challenge produced a rapid reduction in PSD-95 immunoreactivity and prevented the learning-specific increase in the NMDA receptor NR1 subunit and phosphorylated CaMKII. The results show no lasting change in learning-associated molecular events after a neurotoxic MDMA treatment. This drug only produces transient effects on early molecular events involved in memory consolidation, which do not appear to depend on endogenous 5-HT levels.
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PMID:Acute and chronic effects of MDMA on molecular mechanisms implicated in memory formation in rat hippocampus: surface expression of CaMKII and NMDA receptor subunits. 1615 87

The present study investigated the role of inhibitor of protein phosphatases 1 and 2A on the modulation of the phosphorylation of the spinal N-methyl-D-aspartate receptor (NMDAR) NR1 and NR2B subunits following electroacupuncture (EA) stimulation in rats. Bilateral 2Hz EA stimulations with 1.0 mA were delivered at those acupoints corresponding to Zusanli and Sanyinjiao to men via needles for 30 min. EA analgesia was slightly reduced by the intrathecal injection of calyculin A during EA stimulation. At 60 min after the termination of EA stimulation, the levels of c-fos, serine phosphorylation of NR1 and NR2B by Western analysis had increased in the L(4-5) segments of the spinal cord after EA treatment. These expressions were enhanced by the intrathecal injection of calyculin A and immunohistochemical analyses confirmed the significant increase of these proteins. As for the regional reaction of NMDAR subunits, a mean integrated optical density of phosphorylated NR1 and NR2B subunits was potentiated by calyculin A injections in the superficial laminae and neck region and superficial laminae and nucleus proprius, respectively. It can be concluded that protein phosphatase may play an important role in EA analgesia by modulating the phosphorylation state of spinal NMDAR subunits.
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PMID:Effects of protein phosphatase inhibitors on the phosphorylation of spinal cord N-methyl-D-aspartate receptors following electroacupuncture stimulation in rats. 1835 47

This study used immunohistochemistry, Golgi impregnation, and electron microscopy to examine the circuitry of the cerebellum of mormyrid fish. We used antibodies against the following antigens: the neurotransmitters glutamate and gamma-aminobutyric acid (GABA); the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD); GABA transporter 1; the anchoring protein for GABA and glycine receptors, gephyrin; the calcium binding proteins calbindin and calretinin; the NR1 subunit of the N-methyl-D-aspartate glutamate receptor; the metabotropic glutamate receptors mGluR1alpha and mGluR2/3; the intracellular signaling molecules calcineurin and calcium calmodulin kinase IIalpha (CAMKIIalpha); and the receptor for inositol triphosphate (IP3RIalpha). Purkinje cells are immunoreactive to anti-IP3R1alpha, anticalcineurin, and anti-mGluR1alpha. Cerebellar efferent cells (eurydendroid cells) are anticalretinin and anti-NR1 positive in the valvula but not in the corpus and caudal lobe. In contrast, climbing fibers are anticalretinin and anti-NR1 immunopositive in the corpus and caudal lobe but not in the valvula. Purkinje cells, Golgi cells, and stellate cells are GABA positive, whereas efferent cells are glutamate positive. Unipolar brush cells are immunoreactive to anti-mGluR2/3, anticalretinin, and anticalbindin. We describe a "new" cell type in the mormyrid valvula, the deep stellate cell. These cells are GABA, calretinin, and calbindin positive. They are different from superficial stellate cells in having myelinated axons that terminate massively with GAD- and gephyrin-positive terminals on the cell bodies and proximal dendrites of efferent cells. We discuss how the valvula specializations described here may act in concert with the palisade pattern of Purkinje cell dendrites for analyzing spatiotemporal patterns of parallel fiber activity.
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PMID:Morphological analysis of the mormyrid cerebellum using immunohistochemistry, with emphasis on the unusual neuronal organization of the valvula. 1866 56


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