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:2.7.11.17 (CaMKII)
4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diisopropyl phosphorofluoridate (DFP) produces organophosphorus-ester-induced delayed neurotoxicity in sensitive species. We studied the effect of single dose of DFP on the expression of phosphorylated cAMP-response element binding protein (p-CREB), which is a well known transcription factor involved in several pathways mediating different types of external stimuli. The hens were perfused with neutral buffered formalin at different time points, i.e., 0.5, 1.0, and 2.0 hrs, as well as 1, 2, 5, and 20 days after dosing. The central nervous system regions of the whole brain were dissected and 7-micron sections were stained for either p-CREB immunopositivity or with hematoxylin and eosin. Results indicated an early differential increase of p-CREB immunopositivity in susceptible regions such as cerebellum, brainstem, and midbrain within 2 hrs. These induced levels persisted upto 5 days in these tissues, although the time course of p-CREB immunopositivity was distinctly different for each region. In the cerebellum induction of p-CREB was seen in the granular layer where both the granulocytes and the glial cells showed induction. Increased immunopositivity for p-CREB in the Purkinje cells and in some basket cells of the molecular layer was noticed over time, but the induction was not as great as in the granular layer. Of all the tissues cerebellum showed the strongest intensity of immunopositivity of the cells as well as the highest (absolute) number of pCREB-positive cells. The brainstem showed a similar fluctuating pattern like the cerebellum with the highest percentage increase of the immunoreactive cells at 5 days preceded by the lowest dip in immunopositivity at 2 days. In the midbrain, there was a time-dependent increase in the immunopositivity from 0.5 hr onwards until reaching control levels at 20 days. Immunopositivity was also noted in portions of the spina medularis and spina oblongata. The cerebrum (non-susceptible tissue) of DFP-treated hens did not show much deviation from the controls. The endothelial cells of the susceptible regions showed induction at early time points, in contrast to the absence of induction in cerebrum. Spatial and temporal differences in the immunopositivity pattern indicate probable involvement of CREB-independent pathways also. Overall, the complex induction pattern of p-CREB, along with our earlier observations of the early induction of c-fos, c-jun and Protein Kinase A (PKA) as well as the induction of Calcium2+/Calmodulin dependent Protein Kinase II (CaM kinase II) at later periods, strongly suggest an activator role of CREB mediated pathways that may lead to the clinical development of delayed neurotoxicity.
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PMID:Early differential elevation and persistence of phosphorylated cAMP-response element binding protein (p-CREB) in the central nervous system of hens treated with diisopropyl phosphorofluoridate, an OPIDN-causing compound. 1195 15

Mesangial cell growth factors elevate intracellular free [Ca2+]i, but mechanisms linking [Ca2+]i to gene expression and DNA synthesis are unclear. This study investigated the hypothesis that Ca2+/calmodulin-dependent protein kinase II (CaMK II), which is activated by elevated [Ca2+]i, increases c-fos transcription and DNA synthesis via a Src-based mechanism. In cultured rat mesangial cells, dominant negative Src (SrcK-) blocked activation of the c-fos gene promoter by CaMK II 290, a constitutively active form of CaMK IIalpha. Activation of the c-fos promoter by CaMK II 290 was also blocked by COOH-terminal Src kinase, which phosphorylates and inactivates c-Src. A pharmacologic CaMK inhibitor, KN-93, did not block activation of the c-fos promoter by ectopically expressed v-Src. Stimulation of c-Src by endothelin-1 required CaMK II activity, further supporting the notion that CaMK II acts upstream of Src in a signaling cassette. Activation of the c-fos promoter by CaMKII290 and Src required the c-fos serum response element. Dominant negative SrcK- also blocked induction of DNA synthesis in mesangial cells by CaMK II 290. Collectively, these results suggest that in mesangial cells Src protein tyrosine kinases act downstream of CaMKII in a signaling pathway in which [Ca2+]i induces the c-fos promoter and increases DNA synthesis.
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PMID:Ca2+/calmodulin-dependent protein kinase II stimulates c-fos transcription and DNA synthesis by a Src-based mechanism in glomerular mesangial cells. 1250 35

The effects of lead on the signal transduction pathways that may be involved in the release of gonadotropin-releasing hormone (GnRH) from neurons in the hypothalamus have not been well defined. Using the GT1-7 cell line, an in vitro model for GnRH-secreting neurons, we examined signal transduction pathways directly affected by lead. We found that lead-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2), as well as p90RSK and cAMP response element-binding protein (CREB), but did not induce IkappaB degradation. MEK1/2 inhibitor (PD98059) suppressed lead-induced ERK and p90RSK activation. Neither PKC inhibitors (Go6983, Go6976) nor CaMKII inhibitor (KN-62) had a pronounced effect on lead-induced ERK1 and ERK2 phosphorylation. However, MEK1/2 inhibitor, CaMKII inhibitor, and PKC inhibitor significantly suppressed lead-induced CREB phosphorylation. These results indicate that lead-activated PKC, CaMKII and MEK/ERK/p90RSK pathways simultaneously, all of which contributed to CREB phosphorylation. Our results also indicate that lead-induced p90RSK and CREB activation does not alter expression of early response genes like c-fos. We conclude that lead activates PKC, CaMKII or MEK-ERK-p90RSK pathways in GT1-7 cells, leading to CREB phosphorylation and modulation of gene expression.
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PMID:Lead-induced cell signaling cascades in GT1-7 cells. 1283 8

Agrin has been implicated in multiple aspects of central nervous system (CNS) neuron differentiation and function including neurite formation, synaptogenesis, and synaptic transmission. However, little is known about the signaling mechanisms whereby agrin exerts its effects. We have recently identified a neuronal receptor for agrin, whose activation induces expression of c-fos, and provided evidence that agrin binding to this receptor is associated with a rise in intracellular Ca2+, a ubiquitous second messenger capable of mediating a wide range of effects. To gain further insight into agrin's role in brain, we used Ca2+ imaging to explore agrin signal transduction in cultured cortical neurons. Bath application of either z+ or z-agrin isoforms resulted in marked changes in intracellular Ca2+ concentration specifically in neurons. Propagation of the Ca2+ response was a two-step process characterized by an initial increase in intracellular Ca2+ mediated by ryanodine receptor (RyR) release from intracellular stores, supplemented by influx through voltage-gated calcium channels (VGCCs). Agrin-induced increases in intracellular Ca2+ were blocked by genistein and herbimycin, suggesting that the agrin receptor is a tyrosine kinase. Ca2+ release from intracellular stores activates both calcium/calmodulin-dependent kinase II (CaMKII) and mitogen activated protein kinase (MAPK). Activation of CaMKII is required for propagation of the Ca2+ wave itself, whereas both MAPK and CaMKII play a role in mediating long latency responses such as induction of c-fos. These results suggest that an agrin-dependent tyrosine kinase could play a critical role in modulating levels of intracellular Ca2+ and activity of MAPK and CaMKII in CNS neurons.
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PMID:Agrin signaling in cortical neurons is mediated by a tyrosine kinase-dependent increase in intracellular Ca2+ that engages both CaMKII and MAPK signal pathways. 1538 2

The present review focused the involvement of N-methyl-D-aspartate (NMDA) receptors in morphine physical dependence. The increased levels of extracellular glutamate, NMDA receptor zeta subunit (NR1) mRNA, NMDA receptor epsilon 1 subunit (NR2A) protein, phosphorylated Ca(2+)/calmodulin kinase II (p-CaMKII) protein, c-fos mRNA, c-Fos protein, are observed in the specific brain areas of mice and/or rats showing signs of naloxone-precipitated withdrawal. In preclinical and clinical studies, a variety of NMDA receptor antagonists and pretreatment with an antisense oligonucleotide of the NR1 have been reported to inhibit the development, expression and/or maintenance of opiate physical dependence. In contrast to data obtained in adult animals, NMDA receptor antagonists are neither effective in blocking the development of opiate dependence nor the expression of opiate withdrawal in neonatal rats. In the NMDA receptor-deficient mice, the NR2A knockout mice show the marked loss of typical withdrawal abstinence behaviors precipitated by naloxone. The rescue of NR2A protein by electroporation into the nucleus accumbens of NR2A knockout mice reverses the loss of abstinence behaviors. The activation of CaMKII and increased expression of c-Fos protein in the brain of animals with naloxone-precipitated withdrawal syndrome are prevented by NMDA receptor antagonists, whereas the increased levels of extracellular glutamate are not prevented by them. These findings indicate that glutamatergic neurotransmission at the NMDA receptor site contributes to the development, expression and maintenance of opiate dependence, and suggest that NMDA receptor antagonists may be a useful adjunct in the treatment of opiate dependence.
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PMID:Opiate physical dependence and N-methyl-D-aspartate receptors. 1546 26

Significant body of evidence indicates an important role for brain-derived neurotrophic factor (BDNF) in the hippocampal synaptic plasticity; however, the exact mechanisms how the BDNF signal is converted to plastic changes during memory processes are under an intense investigation. To specifically address the role of the trkB receptor, we have previously generated transgenic mice overexpressing the full-length trkB receptor and observed a continuous activation of the trkB.TK+ receptor, improved learning and memory but an attenuated LTP in these mice. In this study, we describe the trkB.TK+ mRNA and protein distribution in the transgenic mice, showing the most prominent increase in the full-length trkB expression in the cortical layer V pyramidal neurons and dentate gyrus of the hippocampus. In addition, we have analyzed the mRNA expression patterns of a group of genes associated with both plastic changes in the nervous system and BDNF signaling. Regulated expression of immediate early genes c-fos, fra-2 and junB was observed in the transgenic mice. Furthermore, the mRNA expression of alpha-Ca2+/calmodulin-dependent kinase II (alpha-CaMKII) was reduced in both the hippocampus and parietal cortex, whereas growth-associated protein 43 (GAP-43) mRNA expressions were induced in the corresponding regions. Conversely, the mRNA expression of the transcription factor cAMP response element binding protein (CREB) was not altered in the trkB.TK+mice. Finally, the density of neuropeptide Y (NPY)-expressing cells was increased in the trkB.TK+ mice dentate hilus. Altogether, these results demonstrate in vivo that the increased trkB.TK+ signaling regulates several important plasticity-related genes.
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PMID:Overexpression of the full-length neurotrophin receptor trkB regulates the expression of plasticity-related genes in mouse brain. 1551 79

Most studies regarding altered gene expression after learning are performed using multi-trial tasks, which do not allow a clear discrimination of memory acquisition, consolidation and retrieval. We screened for candidate memory-modulated genes in the hippocampus at 3 and 24 h after one-trial inhibitory avoidance (IA) training, using a cDNA array containing 1176 genes. While 33 genes were modulated by training (respect to shocked-only animals), most of them were upregulated (27 genes) and only 6 were downregulated. To confirm and extend these findings, we performed RT-PCRs and analyzed differences in protein levels in rat hippocampus using immunoblot assays. We found several proteins upregulated 24 h after training: extracellular signal-regulated kinase ERK2, Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIalpha), Syntaxin 1a, c-fos and Homer 1a. The total level of none of these proteins were found to be altered when measured 3-h post-training. Several of the mRNAs corresponding to the upregulated proteins were changed at 3 h but not 24 h. Additionally, a number of other candidates were identified for the first time as modulated by learning. The results presented here suggest that single-trial tasks can expose previously unseen differences in dynamic regulation of gene expression after behavioral manipulations, both at the transcriptional and translational levels, and reveal a diversity of gene products modulated by this task, allowing deeper understanding of the molecular basis of memory formation.
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PMID:One-trial aversive learning induces late changes in hippocampal CaMKIIalpha, Homer 1a, Syntaxin 1a and ERK2 protein levels. 1554 23

Ca(2+)/calmodulin-dependent protein kinase IIalpha (alpha-CaMKII) was once thought to be exclusively expressed in neuronal tissue, but it is becoming increasingly evident that CaMKII is also expressed in various extraneural cells. CaMKII plays a critical role in regulating various signaling pathways leading to modulation of several aspects of cellular functions, including proliferation, differentiation, cytoskeletal structure, and gene expression. The purpose of this study was to examine the expression of CaMKII in osteoblast-like cells (MC4) and to elucidate its role in osteoblast differentiation. We demonstrated that CaMKII, specifically the alpha isoform, is expressed in osteoblasts both in vitro and in vivo. Inhibition of CaMKII by the calmodulin antagonist trifluoperazine or the CaMKII antagonist KN93 reduces alkaline phosphatase activity and mineralization, as well as causes 85 and 56% decreases in alkaline phosphatase and osteocalcin gene expression, respectively. CaM and CaMKII antagonists, using the newborn mouse calvaria in vivo model, cause a 50% decrease in osteoblast number (N.Ob-BS) and a 32% decrease in mineralization (BV/TV). Pharmacologic and genetic inhibition of alpha-CaMKII by using trifluoperazine, KN93, and alpha-CaMKII small interfering RNA decreases the phosphorylation of ERK and of cAMP-response element-binding protein, leading to a significant decrease in the transactivation of serum response element and cAMP-response element. Inhibition of alpha-CaMKII decreases the expression of c-fos, AP-1 transactivation, and AP-1 DNA binding activity. Our findings demonstrated that alpha-CaMKII is expressed in osteoblasts and is involved in c-fos expression via regulation of serum response element and cAMP-response element. Inhibition of alpha-CaMKII results in a decrease in c-fos expression and AP-1 activation, leading to inhibition of osteoblast differentiation.
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PMID:Calmodulin and calmodulin-dependent kinase IIalpha regulate osteoblast differentiation by controlling c-fos expression. 1559 Jun 32

Behavioral studies have demonstrated that chronic food restriction augments the rewarding and motor-activating effects of centrally injected psychostimulants and direct dopamine (DA) receptor agonists. Recently, it has been shown that intracerebroventricular (i.c.v.) injection of the D-1 DA receptor agonist, SKF-82958, produces an enhanced locomotor-activating effect as well as increased activation of striatal ERK 1/2 MAP kinase, CaM kinase II, CREB, and c-fos in food-restricted (FR) relative to ad libitum fed (AL) rats. Striatal neurons that express the D-1 DA receptor coexpress dynorphin and substance P, and CREB is known to couple D-1 DA receptor stimulation to preprodynorphin (ppD) gene expression. The purpose of the present study was to examine possible genomic consequences of FR using real-time quantitative RT-PCR to measure striatal neuropeptide gene expression 3 h after i.c.v. injection of SKF-82958 (20 microg). Results indicate that, in nucleus accumbens (NAc), basal levels of ppD and preprotachykinin (ppT) mRNA are lower in FR than AL rats. This may reflect a decrease in tonic DA transmission during FR which precedes the compensatory upregulation of postsynaptic D-1 DA receptor-mediated cell signaling. In response to SKF-82958 challenge, however, FR subjects displayed greater levels of ppD and ppT mRNA in NAc than did AL subjects. A similar trend was seen in caudate-putamen (CPu). SKF-82958 also increased preproenkephalin (ppE) mRNA in Nac, but not CPu, with no difference between feeding groups. The present findings regarding ppD and ppT are consistent with prior findings of increased behavioral and cellular responses to acute D-1 DA agonist challenge in FR rats. The functional consequences of increased neuropeptide gene expression in response to acute drug challenge remain to be investigated but may include modulation of behavioral effects that emerge with repeated drug exposure, including sensitization, tolerance, and addiction.
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PMID:Comparison of basal and D-1 dopamine receptor agonist-stimulated neuropeptide gene expression in caudate-putamen and nucleus accumbens of ad libitum fed and food-restricted rats. 1625 73

Activation of c-fos in brain is related to coupling of neuronal activity to gene expression, but also to pathological conditions such as seizures or excitotoxicity-induced cell death. Glutamate activates c-fos in neurons through the calcium-dependent phosphorylation of CREB by ERK and/or CaMKIV kinase pathways downstream NMDA-receptors. In glial cells, however, the activation of c-fos by glutamate is poorly understood. Because glial cells actively modulate neuronal excitability and the brain's response to injury, we studied the mechanisms by which glutamate activates c-fos in rat cortical glial cells. Glutamate potently induced c-fos mRNA in a calcium-dependent manner, as demonstrated by using the calcium chelator BAPTA-AM. Glutamate-induced c-fos mRNA expression was not sensitive to inhibitors of ERK, p38(MAPK), or CaMK pathways, indicating that glial c-fos is activated by a distinct mechanism. Thapsigargin abolished the glutamate effect on c-fos mRNA, indicating ER calcium mobilization. Additionally, glutamate induction of c-fos mRNA was sensitive to the mGluR5 antagonist MPEP but not the NMDA-R antagonist MK-801. In luciferase reporter assays, DRE, which actively represses c-fos by binding the calcium-binding transcriptional repressor DREAM, was activated by glutamate, whereas SRE and CRE were not. Finally, glutamate caused the nuclear export of DREAM in astrocytes, and transfection of astrocytes with a mutant variant of DREAM that constitutively binds DNA inhibited glutamate-induced c-Fos expression. These findings are in sharp contrast to the mechanism described in neurons and suggest a novel pathway activated by glutamate in glial cells that employs mGluR5, ER calcium, and the derepression of c-fos at the DRE.
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PMID:Glutamate activates c-fos in glial cells via a novel mechanism involving the glutamate receptor subtype mGlu5 and the transcriptional repressor DREAM. 1712 Feb 44


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