Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L1, a neural cell adhesion molecule of the immunoglobulin superfamily, is involved in neuronal migration and differentiation and axon outgrowth and guidance. Mutations in the human and mouse L1 gene result in similarly severe neurological abnormalities. To dissociate the functional roles of L1 in the adult brain from developmental abnormalities, we have generated a mutant in which the L1 gene is inactivated by cre-recombinase under the control of the calcium/calmodulin-dependent kinase II promoter. This mutant (L1fy+) did not show the overt morphological and behavioral abnormalities observed previously in constitutive L1-deficient (L1-/-) mice; however, there was an increase in basal excitatory synaptic transmission that was not apparent in L1-/- mice. Similar to L1-/- mice, no defects in short- and long-term potentiation in the CA1 region of the hippocampus were observed. Interestingly, L1fy+ mice showed decreased anxiety in the open field and elevated plus-maze, contrary to L1-/- mice, and altered place learning in the water maze, similar to L1-/- mice. Thus, mice conditionally deficient in L1 expression in the adult brain share some abnormalities, but also display different ones, as compared with L1-/- mice, highlighting the role of L1 in the regulation of synaptic transmission and behavior in adulthood.
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PMID:Decreased anxiety, altered place learning, and increased CA1 basal excitatory synaptic transmission in mice with conditional ablation of the neural cell adhesion molecule L1. 1461 1

Alkaline-induced beta-elimination of phosphate from phosphoserine and phosphothreonine residues followed by addition of an affinity tag has recently been pursued as a strategy for enriching phosphorylated species from complex mixtures. Here we report the use of an introduced thiol tag as the ligand for affinity purification via disulfide exchange with an activated thiol resin and the development of a protocol to improve the sensitivity considerably over previous reports (i.e., to subpicomole levels.) During our experiments, we observed a side reaction in which water was eliminated from unmodified serine residues. This side reaction resulted in the introduction of the affinity tag into unphosphorylated proteins, confounding attempts to specifically purify phosphoproteins from mixtures. Unchecked, this side reaction will also prevent application of the beta-elimination strategy to phosphopeptide samples where the phosphorylated species are minor components (i.e., most current phosphoproteomics applications). Quantitation of the side reaction products using three synthetic unphosphorylated peptides showed varying conversion efficiencies; at maximum, 1.7% of unphosphorylated peptide was converted to the affinity-tagged form. Inclusion of EDTA into the reaction reduced the side reaction but also greatly reduced the conversion efficiency of one of the phosphoserine residues of ovalbumin, suggesting a role for trace metal ions in the beta-elimination chemistry. Despite the presence of the side reaction, the affinity strategy was shown to be effective at enriching phosphopeptides from fairly complex peptide mixtures. The strategy was applied to the analysis of in vitro phosphorylation of bovine synapsin I by Ca(2+)/calmodulin-dependent kinase II, resulting in the identification of four phosphorylation sites, two of which have not been previously reported.
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PMID:Improved beta-elimination-based affinity purification strategy for enrichment of phosphopeptides. 1467 42

NCAM, a neural cell adhesion molecule of the immunoglobulin superfamily, is involved in neuronal migration and differentiation, axon outgrowth and fasciculation, and synaptic plasticity. To dissociate the functional roles of NCAM in the adult brain from developmental abnormalities, we generated a mutant in which the NCAM gene is inactivated by cre-recombinase under the control of the calcium-calmodulin-dependent kinase II promoter, resulting in reduction of NCAM expression predominantly in the hippocampus. This mutant (NCAMff+) did not show the overt morphological and behavioral abnormalities previously observed in constitutive NCAM-deficient (NCAM-/-) mice. However, similar to the NCAM-/- mouse, a reduction in long-term potentiation (LTP) in the CA1 region of the hippocampus was revealed. Long-term depression was also abolished in NCAMff+ mice. The deficit in LTP could be rescued by elevation of extracellular Ca2+ concentrations from 1.5 or 2.0 to 2.5 mm, suggesting an involvement of NCAM in regulation of Ca2+-dependent signaling during LTP. Contrary to the NCAM-/- mouse, LTP in the CA3 region was normal, consistent with normal mossy fiber lamination in NCAMff+ as opposed to abnormal lamination in NCAM-/- mice. NCAMff+ mutants did not show general deficits in short- and long-term memory in global landmark navigation in the water maze but were delayed in the acquisition of precise spatial orientation, a deficit that could be overcome by training. Thus, mice conditionally deficient in hippocampal NCAM expression in the adult share certain abnormalities characteristic of NCAM-/- mice, highlighting the role of NCAM in the regulation of synaptic plasticity in the CA1 region.
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PMID:Conditional ablation of the neural cell adhesion molecule reduces precision of spatial learning, long-term potentiation, and depression in the CA1 subfield of mouse hippocampus. 1497 28

Alpha-tocopherol has been shown to increase nitric oxide (NO)-dependent relaxation but the underlying mechanisms have not been fully characterized. The present study investigates the effect of alpha-tocopherol and its derivative trolox on the synthesis of NO in human umbilical vein endothelial cells. NO was assayed as citrulline (co-product of NO) and cGMP (product of the NO-activated soluble guanylate cyclase) on ionomycin stimulation of cells. Ionomycin induced citrulline and cGMP formation partially through phosphorylation of endothelial NO synthase (eNOS) at its serine residue 1177, which was mediated mainly by calmodulin-dependent kinase II. Preincubation of cells with alpha-tocopherol or trolox increased eNOS activity in a concentration-dependent manner without changing eNOS expression. The effect of the water-soluble trolox was due to chemical stabilization of the eNOS cofactor tetrahydrobiopterin. On the contrary, alpha-tocopherol, located mainly in cellular membranes, did not affect tetrahydrobiopterin but increased ionomycin-induced eNOS phosphorylation at serine 1177. The effects of alpha-tocopherol on citrulline and cGMP formation and eNOS phosphorylation were amplified by co-incubation with ascorbate, which is suggested to regenerate oxidized alpha-tocopherol and to act synergistically with alpha-tocopherol. Our data describe a new vasoprotective function of alpha-tocopherol that may contribute to the prevention of endothelial dysfunction in vivo.
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PMID:Alpha-tocopherol amplifies phosphorylation of endothelial nitric oxide synthase at serine 1177 and its short-chain derivative trolox stabilizes tetrahydrobiopterin. 1528 20

Deletions, translocations, or point mutations in the CREB-binding protein (CBP) gene have been associated with Rubinstein-Taybi Syndrome; a human developmental disorder characterized by retarded growth and reduced mental function. To examine the role of CBP in memory, transgenic mice were generated in which the CaMKII alpha promoter drives expression of an inhibitory truncated CBP protein in forebrain neurons. Examination of hippocampal long-term potentiation (LTP), a form of synaptic plasticity thought to underlie memory storage, revealed significantly reduced late-phase LTP induced by dopamine-regulated potentiation in hippocampal slices from CBP transgenic mice. However, four-train induced late-phase LTP is normal. Behaviorally, CBP transgenic mice exhibited memory deficits in spatial learning in the Morris water maze and deficits in long-term memory for contextual fear conditioning, two hippocampus-dependent tasks. Together, these results demonstrate that CBP is involved in specific forms of hippocampal synaptic plasticity and hippocampus-dependent long-term memory formation.
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PMID:Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage. 1580 5

Hippocampal alpha-Ca2+/calmodulin-dependent protein kinase II (alpha-CaMKII) has been implicated in spatial learning, neuronal plasticity, epilepsy, and cerebral ischemia. In the present study, an adeno-associated virus (AAV) vector was designed to express green fluorescent protein (GFP) from the CBA promoter and a small hairpin RNA targeting alpha-CaMKII (AAV-shCAM) driven from the U6 promoter. The AAV-shCAM or control vector was microinfused into the rat hippocampus and behavioral testing conducted 19-26 days following surgery. Expression of the marker gene and alpha-CaMKII was evaluated 31 days following AAV infusion. GFP expression was localized to the hippocampus and extended +/-2 mm rostral and caudal from the injection site. Hippocampal alpha-CaMKII was significantly reduced following AAV-shCAM treatment as demonstrated using immunohistochemical and Western analysis. This suppression of alpha-CaMKII was associated with changes in exploratory behavior (open field task) and impaired place learning (water maze task). These results demonstrate the efficacy of a viral-based delivered shRNA to produce gene suppression in a specific circuit of the brain.
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PMID:In vivo inhibition of hippocampal Ca2+/calmodulin-dependent protein kinase II by RNA interference. 1592 60

Alpha-calcium/calmodulin-dependent kinase II (alphaCaMKII) is central to synaptic plasticity but it remains unclear whether this kinase contributes to neuronal excitability changes, which are a cellular correlate of learning. Using knock-in mice with a targeted T286A mutation that prevents the autophosphorylation of alphaCaMKII (alphaCaMKII(T286A)), we studied the role of alphaCaMKII signaling in regulating hippocampal neuronal excitability during hippocampus-dependent spatial learning in the Morris water maze. Wild-type control mice showed increased excitability of CA1 pyramidal neurons, as assessed by a reduction in the postburst afterhyperpolarization (AHP), after spatial training in the water maze. Importantly, wild-type mice did not show AHP changes when they were exposed to the water maze without the escape platform and swam the same amount of time as the trained mice (swim controls), thus manifesting learning-specific increases in hippocampal CA1 excitability associated with spatial training. Meanwhile, alphaCaMKII(T286A) mice showed impairments in spatial learning but exhibited reduced levels of AHP that were similar to wild-type controls after water-maze training. Notably, both trained and swim-control groups of alphaCaMKII(T286A) mutants showed similar increased excitability, indicating that swimming by itself is enough to induce changes in excitability in the absence of normal alphaCaMKII function. This result demonstrates dissociation of alphaCaMKII-independent changes in intrinsic neuron excitability from learning and synaptic plasticity mechanisms, suggesting that increases in excitability per se are not perfectly correlated with learning. Our findings suggest that alphaCaMKII signaling may function to suppress learning-unrelated changes during training, thereby allowing hippocampal CA1 neurons to increase their excitability appropriately for encoding spatial memories.
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PMID:Differential effects of alphaCaMKII mutation on hippocampal learning and changes in intrinsic neuronal excitability. 1663 70

The entorhinal cortex functions as the gateway to the hippocampal formation. However, its role in formation and consolidation of hippocampus-dependent memory remains relatively unexplored. In this issue of Neuron, Yasuda and Mayford report an elegant cell-type restricted inducible transgenic mouse overexpressing a mutant form of CaM kinase II selectively in superficial layers of medial entorhinal cortex and its upstream regions. These animals display a selective spatial memory deficit during the immediate posttraining period as well as during acquisition in the Morris water maze. Similar to the hippocampus, this time-limited involvement of entorhinal cortex in spatial memory processing suggests a crucial role for hippocampal-entorhinal circuitry in spatial memory formation.
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PMID:Inducible and cell-type restricted manipulation in the entorhinal cortex. 1663 Aug 40

Environmental enrichment is known to enhance hippocampal neurogenesis and cognitive functions. Neurogranin (Ng), a specific substrate of protein kinase C (PKC), is abundantly expressed in brain regions important for cognitive functions. Deletion of Ng in mice causes severe deficits in spatial learning and long-term potentiation (LTP) in the hippocampal CA1 region. These Ng-/- mice, as compared with Ng+/+, respond poorly after treatment of their hippocampal slices with agents that activate signaling molecules important for learning and memory, including Ca2+/calmodulin-dependent protein kinase II (alphaCaMKII), PKC, protein kinase A (PKA), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB). In the present study, adult mice were housed in either regular home cages (control group) or more spacious cages with an exercise wheel and change of toys twice per week (enriched group) for at least 3 weeks. Enriched Ng+/+ and Ng+/- mice showed enhanced LTP in the hippocampal CA1 after high-frequency stimulation, but Ng-/- mice were affected only minimally. Behaviorally, the enriched Ng+/+ and Ng+/-, but not Ng-/- mice, performed significantly better than their respective control cohorts in Morris water maze and in step-down fear conditioning. Enriched Ng+/- mice also showed improvement in the radial arm maze. Quantitative immunoblot analyses showed that the enriched groups of all three genotypes exhibited elevated hippocampal levels of alphaCaMKII and CREB, but not ERK. Interestingly, enrichment caused a significant increase in hippocampal Ng levels both in Ng+/+ and Ng+/- mice that seemed to contribute to their improved LTP and behavioral performances. These results suggest that Ng gates the neuronal signaling reactions involved in learning and memory. During environmental enrichment, these Ng-regulated reactions are also critical for the enhancement of synaptic plasticity and cognitive functions.
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PMID:Environmental enrichment enhances neurogranin expression and hippocampal learning and memory but fails to rescue the impairments of neurogranin null mutant mice. 1676 30

Transgenic mice in which the tetracycline transactivator (tTA) is driven by the forebrain-specific calcium-calmodulin-dependent kinase II alpha promoter (CaMKII alpha-tTA mice) are used to study the molecular genetics of many behaviors. These mice can be crossed with other transgenic mice carrying a transgene of interest coupled to the tetracycline-responsive promoter element to produce mice with forebrain-specific expression of the transgene under investigation. The value of using CaMKII alpha-tTA mice to study behavior, however, is dependent on the CaMKII alpha-tTA mice themselves lacking a behavioral phenotype with respect to the behaviors being studied. Here we present data that suggest CaMKII alpha-tTA mice have a behavioral phenotype distinct from that of their wild-type (WT) littermates. Most strikingly, we find that CaMKII alpha-tTA mice, both those with a C57BL/6NTac genetic background (B6-tTA) and those with a 129S6B6F1/Tac hybrid genetic background (F1-tTA), exhibit decreased locomotor activity compared with WT littermates that could be misinterpreted as altered anxiety-like behavior. Despite this impairment, neither B6-tTA nor F1-tTA mice perform differently than their WT littermates in two commonly used learning and memory paradigms - Pavlovian fear conditioning and Morris water maze. Additionally, we find data regarding motor coordination and balance to be mixed: B6-tTA mice, but not F1-tTA mice, exhibit impaired performance on the accelerating rotarod and both perform as well as their WT littermates on the balance beam.
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PMID:Decreased locomotor activity in mice expressing tTA under control of the CaMKII alpha promoter. 1764 Feb 89


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