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)

Hippocampal slices were preincubated with 32P-orthophosphate and used to study the effect of glutamate analogs on protein phosphorylation. NMDA induced a rapid, 70% decrease in the phosphorylation of the microtubule-associated protein MAP2, with no change in the total amount of MAP2. Both competitive and noncompetitive NMDA antagonists blocked the effect of NMDA, but a glutamate antagonist acting at non-NMDA receptors did not. Kainate and quisqualate were less potent than NMDA in stimulating dephosphorylation of MAP2. Other forebrain regions (necortex, striatum, and olfactory bulb) also showed dephosphorylation of MAP2 in response to NMDA. These and other results suggest that NMDA receptor activation induces the dephosphorylation of MAP2 by stimulating a protein phosphatase, possibly the calcium/calmodulin-dependent protein phosphatase calcineurin. Moreover, they indicate that alteration in the properties of a microtubule-associated protein may account for some of the effects of glutamate on postsynaptic neurons.
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PMID:Activation of NMDA receptors induces rapid dephosphorylation of the cytoskeletal protein MAP2. 216 65

We examined the effects of chronic treatment with several types of antidepressants on microtubule assembly and phosphorylation of microtubule-associated proteins (MAPs) in the rat cerebral cortex. The microtubule assembly was monitored in turbidity at 350 nm using a spectrophotometer. Chronic but not acute treatment with desipramine (DMI), maprotiline (MPR) or citalopram (CTR) inhibited microtubule assembly, assayed in the presence of protein phosphatase inhibitors (PPI). In contrast, this inhibitory effect was completely nullified in the absence of PPI. The three compounds had no direct effect on microtubule assembly. The phosphorylation of MAPs (MAP2 and tau) was investigated by immunoblotting with monoclonal antibodies (phosphoserine, phosphothreonine and phosphotyrosine) after immunoprecipitation of MAPs. The serine but not threonine or tyrosine phosphorylation of MAP2 was significantly increased after chronic treatment with DMI, MPR or CTR. The phosphorylation of tau was not altered following chronic administration of antidepressants. These results suggest that the inhibition of microtubule assembly observed after chronic antidepressant treatment is attributable to an increase in the phosphorylated MAP2 and this effect may represent a novel and common action of typical and atypical antidepressant agents. Our results show that besides second messengers system, protein phosphorylation might be involved in the therapeutic effects of antidepressants.
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PMID:[Effects of chronic administration of antidepressants on microtubule assembly in rat cerebral cortex]. 856 31

Many activity-dependent changes in synaptic efficacy occur through elevations in postsynaptic calcium triggered by glutamate receptor activation. Here, the postsynaptic, neuron-specific microtubule-associated protein MAP2 is identified as a target of bidirectional calcium-dependent signaling pathways activated by glutamate. Glutamate produced a biphasic change in MAP2: a rapid, transient increase in phosphorylation mediated by metabotropic receptors and attenuated by inhibitors of calcium/calmodulin-dependent protein kinases and protein kinase C, followed by a persistent dephosphorylation of MAP2 mediated by NMDA receptors and activation of the calcium/calmodulin-dependent protein phosphatase 2B (calcineurin). Thus, a single transmembrane signal, glutamate, and the increased intracellular calcium it evokes can have opposing actions on a postsynaptic target phosphoprotein. The phosphorylation state of MAP2 determines its interaction with microtubules and actin filaments, suggesting that glutamatergic regulation of MAP2 phosphorylation may transduce neural activity into modifications in dendritic structure.
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PMID:Postsynaptic mechanisms for bidirectional control of MAP2 phosphorylation by glutamate receptors. 878 50

Pronounced changes in neuronal morphology occur as synapses mature; however, little is known about how synaptic transmission regulates the developing neuronal cytoskeleton. The postsynaptic, microtubule-associated protein MAP2 is a target of multiple, calcium-dependent signaling pathways activated by synaptic transmission. Here we demonstrate that MAP2 phosphorylation is differentially regulated across development. In 32P-labeled hippocampal slices prepared from adult rats, depolarization stimulated a bidirectional change in the phosphorylation of immunoprecipitated MAP2. A transient increase was mediated by metabotropic glutamate receptors (mGluRs) and stimulation of mitogen-activated protein kinases (MAPKs), Ca2+/calmodulin-dependent protein kinases (CaMKs), and protein kinase C (PKC). This increase was followed by a persistent dephosphorylation mediated by NMDA receptors and activation of protein phosphatase 2B (PP2B or calcineurin). In contrast, depolarization of neonatal hippocampal slices stimulated exclusively a net increase in MAP2 phosphorylation, which was attenuated by inhibitors of MAPKs, but not CaMKs or PKC. Furthermore, although incubation in NMDA induced a time-dependent decrease in MAP2 phosphorylation in both adults and neonates, this effect was both less robust and less sensitive to calcineurin inhibitors in neonates than in adults. These data indicate that the mechanisms coupling glutamate release to MAP2 dephosphorylation are relatively lacking in the neonatal hippocampus. Highly phosphorylated MAP2 is impaired in its ability to stabilize microtubules and actin filament bundles in vitro. The neonatal propensity toward glutamate-stimulated MAP2 phosphorylation may serve to reduce cytoskeletal stability and permit dendritic arborization early in postnatal development. In mature neurons, the bidirectional control of MAP2 phosphorylation may participate in activity-dependent synaptic remodeling.
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PMID:Emergence of activity-dependent, bidirectional control of microtubule-associated protein MAP2 phosphorylation during postnatal development. 892 19

A survival-promoting peptide has been purified from medium conditioned by Y79 human retinoblastoma cells and a mouse hippocampal cell line (HN 33.1) exposed to H2O2. A 30 residue synthetic peptide was made on the basis of N-terminal sequences obtained during purification, and it was found to exhibit gel mobility and staining properties similar to the purified molecules. The peptide maintains cells and their processes in vitro for the HN 33.1 cell line treated with H2O2, and in vivo for cortical neurons after lesions of the cerebral cortex. It has weak homology with a fragment of a putative bacterial antigen and, like that molecule, binds IgG. The peptide also contains a motif reminiscent of a critical sequence in the catalytic region of calcineurin-type phosphatases; surprisingly, like several members of this family, the peptide catalyzes the hydrolysis of para-nitrophenylphosphate in the presence of Mn2+. Application of the peptide to one side of bilateral cerebral cortex lesions centered on area 2 in rats results in an increase in IgG immunoreactivity in the vicinity of the lesions 7 d after surgery. Microglia immunopositive for IgG and ED-1 are, however, dramatically reduced around the lesions in the treated hemisphere. Furthermore, pyramidal neurons that would normally shrink, die, or disintegrate were maintained, as determined by MAP2 immunocytochemistry and Nissl staining. These survival effects were often found in both hemispheres. The results suggest that this peptide operates by diffusion to regulate the immune response and thereby rescue neurons that would usually degenerate after cortical lesions. The phosphatase activity of this molecule also suggests the potential for direct neuron survival-promoting effects.
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PMID:Identification of a survival-promoting peptide in medium conditioned by oxidatively stressed cell lines of nervous system origin. 973 29

Abnormally hyperphosphorylated tau which is the major protein subunit of paired helical filaments (PHF)/neurofibrillary tangles is the pivotal lesion in Alzheimer disease (AD) and related tauopathies. The cosegregation of tau mutations with disease in inherited cases of frontotemporal dementia has confirmed that abnormalities in this protein can be a primary cause of neurodegeneration. Unlike normal tau that promotes assembly and maintains the structure of microtubules, the abnormally hyperphosphorylated protein sequesters normal tau, MAP1 and MAP2 and consequently disassembles microtubules. The abnormal hyperphosphorylation also promotes the self assembly of tau into tangles of PHF. The hyperphosphorylation of tau in AD is probably due to a protein phosphorylation/dephosphorylation imbalance produced by a decrease in the activity of protein phosphatase (PP)-2A and increase in the activities of tau kinases which are directly or indirectly regulated by PP-2A. Two of the most promising pharmacologic therapeutic approaches to AD are (1) the development of drugs that can inhibit the sequestration of normal MAPs by the abnormally hyperphosphorylated tau, and (2) the development of drugs that can reverse the abnormal hyperphosphorylation of tau by correcting the protein phosphorylation/dephosphorylation imbalance.
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PMID:Significance and mechanism of Alzheimer neurofibrillary degeneration and therapeutic targets to inhibit this lesion. 1221 1

Neurofibrillary degeneration appears to be required for the clinical expression of Alzheimer disease (AD) and related tauopathies. Given the polyetiology of these diseases and the pivotal involvement of neurofibrillary degeneration in their pathogenesis, inhibition of this lesion offers a promising therapeutic target. Studies from our laboratories have shown that there is a protein phosphorylation/dephosphorylation imbalance and that the microtubule associated protein tau is abnormally hyperphosphorylated in the brain of patients with AD and in this form it is the major protein subunit of paired helical filaments/neurofibrillary tangles (PHF/NFT). The abnormal tau which is polymerized into PHF/NFT neither promotes or inhibits in vitro microtubule assembly. In contrast the cytosolic abnormally hyperphosphorylated tau from AD brain, the AD P-tau neither associates with tubulin nor promotes in vitro microtubule assembly but instead it sequesters normal tau, MAP1 and MAP2 and inhibits microtubule assembly. The AD P-tau readily self-assembles in vitro into tangles of PHF/straight filaments under physiological conditions of protein concentration, pH, ionic strength and reducing conditions and this self assembly requires the abnormal hyperphosphorylation of this protein. The activity of phosphoseryl/phosphothreonyl protein phosphatase (PP)-2A which regulates the phosphorylation of tau, is compromised in AD brain. Thus, modulation of the activities of protein phosphatase-2A and tau kinases and inhibition of the sequestration of normal MAPs by AD P-tau offer promising therapeutic opportunities to inhibit neurofibrillary degeneration and the diseases characterized by this lesion.
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PMID:Pharmacological targets to inhibit Alzheimer neurofibrillary degeneration. 1245 74

Neurofibrillary degeneration has primary and pivotal involvement in the pathogenesis of Alzheimer disease (AD) and other tauopathies. The inhibition of this lesion offers a promising therapeutic approach. The microtubule- associated protein (MAP) tau is abnormally hyperphosphorylated in the brain of patients with AD, and in this form it is the major protein subunit of paired helical filaments/neurofibrillary tangles (PHF/NFT). The abnormal tau that is polymerized into PHF/NFT is apparently inert and has no effect on microtubule assembly in vitro. The cytosolic abnormally hyperphosphorylated tau from AD brain, the AD P-tau, does not promote in vitro microtubule assembly but, instead, sequesters normal tau, MAP1, and MAP2 and inhibits microtubule assembly. The AD P-tau readily self-assembles in vitro into tangles of PHF/straight filaments, and this self-assembly requires the abnormal hyperphosphorylation of this protein. Although, to date, an up-regulation of the activity of a tau kinase has not been established, the activity of phosphoseryl/ phosphothreonyl protein phosphatase (PP)-2A, which regulates the phosphorylation of tau, is compromised in AD brain. Thus, modulation of the activities of pp-2A and one or more tau kinases and inhibition of the sequestration of normal MAPs by AD P-tau offer promising therapeutic opportunities to inhibit neurofibrillary degeneration and the diseases characterized by this lesion. Development of high-throughput screening assays for potential drugs aimed at these therapeutic targets is currently under way.
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PMID:Alzheimer neurofibrillary degeneration: therapeutic targets and high-throughput assays. 1450 Oct 27

Neurofibrillary degeneration (ND) is both a pivotal and a primary lesion of Alzheimer disease (AD) and related tauopathies. To date in all known tauopathics including AD, the neurofibrillary changes, whether of paired helical filaments (PHF), twisted ribbons or straight filaments (SF) are made up of abnormally hyperphosphorylated tau, and the number of these lesions directly correlates to the degree of dementia in the affected individuals. Unlike normal tau which promotes assembly and maintains structure of microtubules, the abnormal tau not only lacks these functions but also sequesters normal tau, MAPI and MAP2, and causes disassembly of microtubules. This toxic behavior of the abnormal tau is solely due to its hyperphosphorylation because dephosphorylation restores it into a normal-like protein. The abnormal hyperphosphorylation also promotes the self-assembly of tau into PHF/SF. Missense mutations in tau that cosegregate with the disease in inherited cases of frontotemporal dementia make it a more favorable substrate for hyperphosphorylation. A cause of the abnormal hyperphosphorylation in AD brain is a decrease in the activity of protein phosphatase (PP)-2A, a major regulator of the phosphorylation of tau. The abnormal hyperphosphorylation of tau and neurofibrillary degeneration may be inhibited by increasing the activity of PP-2A, inhibiting the activity of one or more tau kinases or by the sequestration of normal tau by the abnormally hyperphosphorylated tau. A great advantage of developing therapeutic drugs to inhibit neurofibrillary degeneration is that the efficacy of these drugs can be monitored by assaying the CSF levels of phosphotau and total tau, both of which are elevated in AD. Thus, the development of drugs that inhibit neurofibrillary degeneration is a very promising and feasible therapeutic approach to AD and related tauopathies.
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PMID:Inhibition of neurofibrillary degeneration: a promising approach to Alzheimer's disease and other tauopathies. 1527 Jan 96

Just as neuronal activity is essential to normal brain function, microtubule-associated protein tau appears to be critical to normal neuronal activity in the mammalian brain, especially in the evolutionary most advanced species, the homo sapiens. While the loss of functional tau can be compensated by the other two neuronal microtubule-associated proteins, MAP1A/MAP1B and MAP2, it is the dysfunctional, i.e., the toxic tau, which forces an affected neuron in a long and losing battle resulting in a slow but progressive retrograde neurodegeneration. It is this pathology which is characteristic of Alzheimer disease (AD) and other tauopathies. To date, the most established and the most compelling cause of dysfunctional tau in AD and other tauopathies is the abnormal hyperphosphorylation of tau. The abnormal hyperphosphorylation not only results in the loss of tau function of promoting assembly and stabilizing microtubules but also in a gain of a toxic function whereby the pathological tau sequesters normal tau, MAP1A/MAP1B and MAP2, and causes inhibition and disruption of microtubules. This toxic gain of function of the pathological tau appears to be solely due to its abnormal hyperphosphorylation because dephosphorylation converts it functionally into a normal-like state. The affected neurons battle the toxic tau both by continually synthesizing new normal tau and as well as by packaging the abnormally hyperphosphorylated tau into inert polymers, i.e., neurofibrillary tangles of paired helical filaments, twisted ribbons and straight filaments. Slowly but progressively, the affected neurons undergo a retrograde degeneration. The hyperphosphorylation of tau results both from an imbalance between the activities of tau kinases and tau phosphatases and as well as changes in tau's conformation which affect its interaction with these enzymes. A decrease in the activity of protein phosphatase-2A (PP-2A) in AD brain and certain missense mutations seen in frontotemporal dementia promotes the abnormal hyperphosphorylation of tau. Inhibition of this tau abnormality is one of the most promising therapeutic approaches to AD and other tauopathies.
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PMID:Tau pathology in Alzheimer disease and other tauopathies. 1561 38


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