Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sexual differentiation of reproductive physiology and behavior in the rodent brain is largely determined by estradiol aromatized from testicular androgens. The cellular mechanisms by which estradiol masculinizes the brain are beginning to emerge and revealing novel features of brain development that are highly region-specific. In the preoptic area, the major site controlling male sexual behavior, estradiol increases the level of the COX-2 enzyme and its product, prostaglandin E2 which promotes dendritic spine synaptogenesis. In the ventromedial nucleus of the hypothalamus, the major site controlling female reproductive behavior, estradiol promotes glutamate release from synaptic terminals, activating NMDA receptors and the MAP kinase pathway. In the arcuate nucleus, a major regulator of anterior pituitary function, estradiol increases GABA synthesis, altering the morphology of neighboring astrocytes and reducing formation of dendritic spines synapses. Glutamate, GABA and the importance of neuronal-astrocytic cross-talk are emerging as common aspects of masculinization. Advances are also being made in the mechanistic basis of female brain development, although the challenges are far greater.
 ...
PMID:Cellular mechanisms of estradiol-mediated masculinization of the brain. 1843 May 66

In the present study, we prepared a SCA3 animal model by generating transgenic mice expressing polyglutamine-expanded ataxin-3-Q79. Ataxin-3-Q79 was expressed in brain areas implicated in SCA3 neurodegeneration, including cerebellum, pontine nucleus and substantia nigra. Ataxin-3-Q79 transgenic mice displayed motor dysfunction with an onset age of 5-6 months, and neurological symptoms deteriorated in the following months. A prominent neuronal loss was not found in the cerebellum of 10 to 11-month-old ataxin-3-Q79 mice displaying pronounced ataxic symptoms, suggesting that instead of neuronal demise, ataxin-3-Q79 causes neuronal dysfunction of the cerebellum and resulting ataxia. To test the involvement of transcriptional dysregulation in ataxin-3-Q79-induced cerebellar malfunction, microarray analysis and real-time RT-PCR assays were performed to identify altered cerebellar mRNA expressions of ataxin-3-Q79 mice. Compared to non-transgenic mice or mice expressing wild-type ataxin-3-Q22, 10 to 11-month-old ataxin-3-Q79 mice exhibited downregulated mRNA expressions of proteins involved in glutamatergic neurotransmission, intracellular calcium signaling/mobilization or MAP kinase pathways, GABA(A/B) receptor subunits, heat shock proteins and transcription factor regulating neuronal survival and differentiation. Upregulated expressions of Bax, cyclin D1 and CDK5-p39, which may mediate neuronal death, were also observed in ataxin-3-Q79 transgenic mice. The involvement of transcriptional abnormality in initiating the pathological process of SCA3 was indicated by the finding that 4 to 5-month-old ataxin-3-Q79 mice, which did not display neurological phenotype, exhibited downregulated mRNA levels of genes involved in glutamatergic signaling and signal transduction. Our study suggests that polyglutamine-expanded ataxin-3 causes cerebellar dysfunction and ataxia by disrupting the normal pattern of gene transcriptions.
 ...
PMID:Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation. 1850 40

The developmental effects of thyroid hormones (TH) in mammalian brain are mainly mediated by nuclear receptors regulating gene expression. However, there are increasing evidences of nongenomic mechanisms of these hormones associated with kinase- and calcium-activated signaling pathways. In this context, the aim of the present work was to investigate the signaling pathways involved in the mechanism of action of TH on cytoskeletal phosphorylation in cerebral cortex of 15-day-old male rats. Results showed that L-thyroxine (L-T4) increased the intermediate filament (IF) phosphorylation independently of protein synthesis, without altering the total immunocontent of these proteins. Otherwise, neither 3,5,3'-triiodo-L-thyronine (L-T3) nor neurotransmitters (GABA, ATP, L-glutamate or epinephrine) acted on the IF-associated phosphorylation level. We also demonstrated that the mechanisms underlying the L-T4 effect on the cytoskeleton involve membrane initiated actions through Gi protein-coupled receptor. This evidence was reinforced by the inhibition of cyclic adenosine 5'-monophosphate (cAMP) levels. Moreover, we showed the participation of phospholipase C, protein kinase C, mitogen-activated protein kinase, calcium/calmodulin-dependent protein kinase II, intra- and extracellular Ca2+ mediating the effects of L-T4 on the cytoskeleton. Stimulation of 45Ca2+ uptake by L-T4 was also demonstrated. These findings demonstrate that L-T4 has important physiological roles modulating the cytoskeleton of neural cells during development.
 ...
PMID:Nongenomic actions of thyroxine modulate intermediate filament phosphorylation in cerebral cortex of rats. 1876 Mar 34

A method to evaluate kinase inhibitor action was reported [L. Morgan, S.J. Neame, H. Child, R. Chung, B. Shah, L. Barden, J.M. Staddon, T.R. Patel, Development of a pentylenetetrazole-induced seizure model to evaluate kinase inhibitor efficacy in the central nervous system, Neurosci. Lett. 395 (2006) 143-148]. In this, acute administration of the GABA antagonist pentylenetetrazole triggers seizures through glutamate-dependent pathways. Under such conditions, activation of the c-Jun N-terminal kinase (JNK) pathway was detected in hippocampal extracts. Phosphorylation of the upstream JNK kinase MKK4 was also revealed through use of a phospho-MKK4-specific antibody. Here, this antibody is shown to also react with a protein of approximately 125 kDa which underwent increased phosphorylation in response to pentylenetetrazole treatment. The present study aimed to identify the approximately 125 kDa protein as it may provide novel insight into signalling, neuronal activity and seizures. Using chromatographic methods and mass spectrometry, the protein was identified as amphiphysin I. This was confirmed by 2D gel analysis and immunoblot with amphiphysin I-specific antibodies. Although the phospho-MKK4 antibody was raised against an MKK4-specific peptide, partial sequence homology between this sequence and a region of amphiphysin was discerned. New antibodies raised against the phospho-threonine 260-amphiphysin-specific sequence detected increased phosphorylation in response to pentylenetetrazole treatment. This particular phosphorylation site does not seem to have been described before, possibly reflecting a novel regulatory aspect of amphiphysin biology. As amphiphysin is involved in the regulation of endocytosis, phosphorylation at this site may play a role in the regulated re-uptake of synaptic vesicles after neurotransmitter release.
 ...
PMID:Amphiphysin I phosphorylation on residue threonine 260 in a pentylenetetrazole-induced seizure model. 1876 Oct 55

Gene expression changes in neuropsychiatric and neurodegenerative disorders, and gene responses to therapeutic drugs, provide new ways to identify central nervous system (CNS) targets for drug discovery. This review summarizes gene and pathway targets replicated in expression profiling of human postmortem brain, animal models, and cell culture studies. Analysis of isolated human neurons implicates targets for Alzheimer's disease and the cognitive decline associated with normal aging and mild cognitive impairment. In addition to tau, amyloid-beta precursor protein, and amyloid-beta peptides (Abeta), these targets include all three high-affinity neurotrophin receptors and the fibroblast growth factor (FGF) system, synapse markers, glutamate receptors (GluRs) and transporters, and dopamine (DA) receptors, particularly the D2 subtype. Gene-based candidates for Parkinson's disease (PD) include the ubiquitin-proteosome system, scavengers of reactive oxygen species, brain-derived neurotrophic factor (BDNF), its receptor, TrkB, and downstream target early growth response 1, Nurr-1, and signaling through protein kinase C and RAS pathways. Increasing variability and decreases in brain mRNA production from middle age to old age suggest that cognitive impairments during normal aging may be addressed by drugs that restore antioxidant, DNA repair, and synaptic functions including those of DA to levels of younger adults. Studies in schizophrenia identify robust decreases in genes for GABA function, including glutamic acid decarboxylase, HINT1, glutamate transport and GluRs, BDNF and TrkB, numerous 14-3-3 protein family members, and decreases in genes for CNS synaptic and metabolic functions, particularly glycolysis and ATP generation. Many of these metabolic genes are increased by insulin and muscarinic agonism, both of which are therapeutic in psychosis. Differential genomic signals are relatively sparse in bipolar disorder, but include deficiencies in the expression of 14-3-3 protein members, implicating these chaperone proteins and the neurotransmitter pathways they support as possible drug targets. Brains from persons with major depressive disorder reveal decreased expression for genes in glutamate transport and metabolism, neurotrophic signaling (eg, FGF, BDNF and VGF), and MAP kinase pathways. Increases in these pathways in the brains of animals exposed to electroconvulsive shock and antidepressant treatments identify neurotrophic and angiogenic growth factors and second messenger stimulation as therapeutic approaches for the treatment of depression.
 ...
PMID:Target identification for CNS diseases by transcriptional profiling. 1892 5

Valproic acid (VPA), a drug used to treat epilepsy and bipolar mood disorder, inhibits histone deacetylase (HDAC), which is associated with the epigenetic regulation of gene expression. Using a microarray, we comprehensively examined which genes are affected by stimulating cultured rat cortical neurons with VPA, and found that the VPA-treatment markedly altered gene expression (up-regulated; 726 genes, down-regulated; 577 genes). The mRNA expression for brain-derived neurotrophic factor (BDNF) and the alpha4 subunit of the GABA(A) receptor (GABA(A)Ralpha4), known to be involved in epileptogenesis, was up-regulated, with the increase in BDNF exon I-IX mRNA expression being remarkable, whereas that for GABA(A)Rgamma2, GAD65 and 67, and the K(+)/Cl(-) co-transporter KCC2, which are responsible for the development of GABAergic inhibitory neurons, was down-regulated. The number of GAD67-positive neurons decreased upon VPA-treatment. Similar changes of up- and down-regulation were obtained by trichostatin A. VPA did not affect the intracellular Ca(2+) concentration and the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), suggesting its direct action on HDAC. The acetylation of histones H3 and H4 was increased in the promoters of up-regulated but not down-regulated genes. Thus, VPA may disrupt a balance between excitatory and inhibitory neuronal activities through its epigenetic effect.
 ...
PMID:Valproic acid induces up- or down-regulation of gene expression responsible for the neuronal excitation and inhibition in rat cortical neurons through its epigenetic actions. 1946 67

Affective disorders are often accompanied by changes in motivation and anxiety. We investigated the genome-wide gene expression patterns in an animal model of depression that separates Wistar rats belonging into clusters of persistently high anxiety/low motivation to explore and low anxiety/high motivation to explore (low explorers and high explorers, LE and HE, respectively), in three brain regions previously implicated in mood disorders (raphe, hippocampus and the frontal cortex). Several serotonin-, GABA-, and glutamatergic genes were differentially expressed in LE- and HE-rats. The analysis of Gene Ontology biological process terms associated with the differentially regulated genes identified a significant overrepresentation of genes involved in the neuron development, morphogenesis, and differentiation; the most enriched pathways from the Kyoto Encyclopedia of Genes and Genomes were the Wnt signalling, MAPK signalling, long-term potentiation, and long-term depression pathways. These findings corroborate some expression data from other models of depression, and suggest additional targets.
 ...
PMID:Differential gene expression in a rat model of depression based on persistent differences in exploratory activity. 1985 24

GABA, the principal inhibitory neurotransmitter in the adult brain, has a parallel inhibitory role in the immune system. We demonstrate that immune cells synthesize GABA and have the machinery for GABA catabolism. Antigen-presenting cells (APCs) express functional GABA receptors and respond electrophysiologically to GABA. Thus, the immune system harbors all of the necessary constituents for GABA signaling, and GABA itself may function as a paracrine or autocrine factor. These observations led us to ask further whether manipulation of the GABA pathway influences an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Increasing GABAergic activity ameliorates ongoing paralysis in EAE via inhibition of inflammation. GABAergic agents act directly on APCs, decreasing MAPK signals and diminishing subsequent adaptive inflammatory responses to myelin proteins.
 ...
PMID:Inhibitory role for GABA in autoimmune inflammation. 2013 56

Cerebellar mechanisms were explored underlying the effects of amphetamine (Amph) on the brain, by monitoring primarily the neurochemistry of the cerebellum. Adult mice received repeated intermittent injections of d-Amph, 5mg/kg or saline, twice daily for three days and once on day 4. As revealed by the biochemical analysis, the levels of GABA content were increased by 68-93% in the cerebellar vermis and hemisphere of mice at 4h after the first (acute) or the last (repeated) Amph injections, though the glutamate content was unaltered, compared to the respective saline-treated controls. By contrast, at 4h post-repeated Amph, in the vermis, the level of norepinephrine was approximate 38% lower than the corresponding control and 5-hydroxytryptamine (5-HT) resembled the control, whereas in the hemisphere, the norepinephrine content was similar to control and 5-HT 66% higher, implying cerebellar lobe-dependent changes. However, in both lobes, at 4h after the acute and repeated Amph exposures, changes of the transmitter content were correlated with reductions of 50-64% in the levels of the phosphorylated (p) MAP kinase (K) expression and 39-55% in the calbindin-D28k (CB) of the Purkinje cell somata, and increases of 289-556% in pCREB, 373-594% c-FOS, and 51-76% calretinin of the granular layer, as shown by immunohistochemical analysis. The up-regulated GABA content in the vermis and hemisphere may be associated with the decreased expression of Purkinje somatal CB and pMAPK, implicating a relation between the Ca(2+) of Purkinje cells and the level of GABA. Furthermore, the prominent increases of the granular layer pCREB, c-FOS and calretinin may influence the activity of Purkinje cells, which are known to be modulated by the granule cells. The data indicate that the Amph exposure selectively alters specific transmitters in the cerebellar lobes and modifies the cellular expression of distinct signaling proteins in the cerebellar layers.
 ...
PMID:Differential changes in cerebellar transmitter content and expression of calcium binding proteins and transcription factors in mouse administered with amphetamine. 2060 Apr 41

Propofol (2,6-diisopropylphenol), one of the most commonly used intravenous anaesthetic agents during cancer resection surgery, has been reported to have the ability of influencing the invasion of human cancer cells. In the present study, using the human colon carcinoma cell line LOVO, we demonstrated that propofol stimulation significantly decreased the expression of MMP-2 and -9 and subsequently decreased the invasive activity of the cancer cells. Because MAPK signaling is one of the key regulators of MMP expression, we further evaluated MAPK signaling after stimulation with propofol. It was found that propofol stimulation inhibited the phosphorylation of MAPKs, including ERK1/2, JNK, and p38. Deactivation of ERK1/2 phosphorylation was sustained for up to 12h, while deactivation of phosphorylation of JNK and p38 returned to the endogenous level by 30 min. It was noteworthy that the ras/raf/MEK/ERK pathway inhibitor PD98059 attenuated the down-regulation of propofol-induced MMP-9 expression of LOVO cells. We also demonstrated that the propofol-induced decrease in invasive ability via ERK1/2 down-regulation was mediated mainly through the GABA-A receptor. These results indicate that propofol stimulation inhibits cancer cell invasion and that the effect is partly due to ERK1/2-dependent down-regulation of MMPs.
 ...
PMID:GABA-receptor agonist, propofol inhibits invasion of colon carcinoma cells. 2088 81


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>