Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A rise in Ca2+ concentration at postsynaptic sites provides an initial step in inducing both the long-term potentiation (LTP) and long-term depression (LTD) in the CA1 region of the hippocampus. LTP induction requires the activation of Ca(2+)-sensitive protein kinases following the rise in Ca2+. By contrast, the activity of protein phosphatase(s) appears to be critical to induce LTD. Here we demonstrate that inhibition of the synthesis of calcineurin A alpha and A beta, catalytic subunits of Ca2+/calmodulin- (CaM) dependent protein phosphatase, reduces the threshold of induction for commissural-CA1 LTP in anesthetized rats. In rats administered antisense oligodeoxynucleotides (ODNs) against calcineurin A alpha and A beta intraventricularly for 7 days, a brief tetanic stimulation to the CA3 region, which in the control case was below threshold for the induction of LTP, now produced a long-lasting increase in both the EPSP slope and the amplitude of population spike recorded from the commissural-CA1 pathway. Western blot analysis of calcineurin showed that the threshold reduction was accompanied by a selective decrease in the protein levels in the hippocampus. Thus our study provides direct evidence that calcineurin per se has an antagonizing role in LTP induction. Complementary experiments with the selective calcineurin inhibitor, FK506, also showed the reduction of LTP threshold in a dose-dependent manner. These results, together with previous studies, support the hypothesis that the quantitative phosphorylation level of critical intracellular proteins determines whether the synaptic efficacy will increase or decrease after the activity-dependent rise in postsynaptic Ca2+.
Brain Res Mol Brain Res 1996 Sep 05
PMID:A facilitatory effect on the induction of long-term potentiation in vivo by chronic administration of antisense oligodeoxynucleotides against catalytic subunits of calcineurin. 888 51

Using in situ hybridization, Northern blotting and RT-PCR we studied the post-ischemic expression of bcl-2, bcl-x, bax and ICE. One day following 5 min or 10 min of global ischemia bcl-2 and bcl-x mRNAs were induced in CA1 hippocampal pyramidal neurons while bax was unchanged. By 72 h after ischemia the expression of bcl-2, bcl-x and bax mRNAs decreased in CA1. The large isoform of bcl-x (bcl-xL), detected using RT-PCR, decreased in whole hippocampus by 24-72 h after ischemia relative to the putative short (bcl-xS) and transmembrane deleted (bcl-x delta TM) forms. Oligonucleotides to interleukin-1 beta convertase (ICE), which detected the expected 2-kb transcript and two lesser 1.5- and 3-kb hybridizing species, demonstrated slight mRNA induction in the CA1 region at 72 h following ischemia. DNA nick end-labeling at 3 days following ischemia showed DNA fragmentation in neurons limited to the CA1 region of hippocampus following 5 min ischemia, while DNA fragmentation was detected in CA1, CA3, dentate gyrus and cortical neurons following 10 min ischemia. The data support the view that hippocampal neurons might undergo an apoptosis-like death after global ischemia. Since global ischemia decreases total protein synthesis especially in the CA1 region, the increases in bcl-2 mRNA levels may not necessarily lead to increased Bcl-2 protein levels. This may explain why the CA1 neurons die despite the prominent induction of the protective bcl-2 gene. The observed decrease by 24 h in the bcl-xL/bcl-xS ratio which preceded DNA fragmentation may participate in the cell death produced by ischemia. However, because of the ischemia-induced decrease in total protein synthesis, the decreased bcl-xL/bcl-xS ratio does not necessarily lead to a changed ratio in the amount of the appropriate proteins. Since ICE-like mRNA was induced at 72 h when the CA1 neurons were dead, the significance of this ICE-like mRNA induction remains unclear.
Brain Res Mol Brain Res 1996 Nov
PMID:Global ischemia induces apoptosis-associated genes in hippocampus. 891 83

Ubiquitin gene expression following transient forebrain ischemia in the rat was analyzed by three probes which were specific for UbC, UbB and UbS30 mRNA. According to the in situ hybridization studies, each type of ubiquitin gene expression decreased at 30 min of reperfusion following 20 min of forebrain ischemia, thereafter increased, and then reached a peak at 4-6 h, both in the cortex and hippocampus. These changes returned to the control level after 24-48 h of recirculation. Among the three ubiquitin transcripts, changes in UbC expression were more marked in the hippocampus, and persistent expression of UbC transcripts in the CA1 and CA3 regions was observed at 24 h of reperfusion. With dot-blot analysis, significant increases in the UbC transcripts were noted at 4 h of reperfusion in the hippocampus, and at 6 h in the cortex following 20 min of ischemia. These results suggest that changes in UbC expression might be a good indicator of ischemic stress.
Brain Res Mol Brain Res 1996 Mar
PMID:Ubiquitin gene expression following transient forebrain ischemia. 896 46

Although glutamatergic receptors are localized throughout the mammalian central nervous system (CNS), the specific cellular localization of the various glutamatergic receptor subtypes throughout human brain remains largely unknown. PCR fragments to human GluR1, GluR2, and GluR3 receptor subtypes were cloned and used as probes for in situ hybridization in order to examine the anatomical and cellular localization of glutamate receptor subtype gene expression in dissected regions of human postmortem brain tissue. Although hybridization was observed throughout the CNS, results indicated that the highest levels of hybridization were in the hippocampus, with localization primarily to cells in the pyramidal cell layer of the CA1-CA3 region, and the granular cells of the dentate gyrus. Prominent hybridization also was observed in the medium to large neurons of the cingulate cortex, temporal lobe, septum, and amygdala, as well as in scattered neurons in the thalamus, cerebral cortex, and medulla. A striking pattern of differential hybridization was observed within the cerebellum. GluR1 demonstrated light hybridization along the Purkinje/Bergmann glia layer, with GluR2 and GluR3 demonstrating hybridization to Purkinje cells, and GluR3 also to cells within the molecular layer, previously identified as stellate-basket cells. Changes in glutamate receptor function have been shown to be important in the pathogenesis of a number of neurological disorders. Therefore, an examination of glutamatergic receptor expression in human postmortem brain tissue may provide important information on the molecular basis of a variety of neurological and psychiatric disorders of the CNS.
J Mol Neurosci 1996
PMID:Regional gene expression of the glutamate receptor subtypes GluR1, GluR2, and GluR3 in human postmortem brain. 896 49

The expression of junD was studied in the rat hippocampus by in situ hybridization after 15 min of normothermic (37 degrees C) and hypothermic (33 degrees C) transient forebrain ischemia. Ischemia was induced by common carotid artery occlusion combined with hypotension leading to damage in the CA1 region of the hippocampus which was prevented by hypothermia. junD mRNA was induced in the hippocampus within 2 h of reperfusion and was strong in the dentate gyrus but weak in the CA3 and CA1 subregions. Intraischemic hypothermia significantly augmented the junD induction in the dentate gyrus. During late reperfusion (between 12 and 36 h after ischemia) a transient increase in junD mRNA was seen in the normothermic CA3 which was abolished in the hypothermic brains. In contrast, in the normothermic CA1 a continuous increase of junD was seen. This was significantly reduced by intraischemic hypothermia. We suggest that the early induction in junD expression in the dentate gyrus and in the hypothermic CA3 region is a protective reaction to the ischemic stress. The marked increase in resistant brain areas could be due to the preserved intracellular signaling pathways and a subsequent maintenance of protein synthesis. The late continuous increase, unique to the vulnerable normothermic CA1 region, suggests that junD participates in a transcriptional process that may be important for delayed neuronal death in the hippocampus following transient forebrain ischemia.
Brain Res Mol Brain Res 1996 Dec 31
PMID:Induction of junD mRNA after transient forebrain ischemia in the rat. Effect of hypothermia. 903 18

Kindling is a well documented model of acquired focal epilepsy and synaptic plasticity in the nervous system. Previous biochemical studies have indicated an increase in mGluR-mediated phosphoinositide hydrolysis in the amygdala or hippocampus of fully kindled animals. In this study we have used in situ hybridisation techniques to examine the mRNA expression of group I metabotropic glutamate receptors (mGluR1 and mGluR5 both linked to phosphoinositide hydrolysis) in the hippocampus of amygdala-kindled animals sacrificed 24 h, 7 days or 28 days following the last electrically evoked stage 5 seizure, and in implanted non-stimulated control rats. Results indicate an initial up-regulation in mGluR1 mRNA (expressed as percentage of control) bilaterally in the DG (35-40%) and CA3 (16-48%), and unilaterally in CA4 (12%) in the 24 h post-kindled group. In kindled animals studied 7 days after the last seizure, these changes were either reduced or had returned to control levels. By 28 days mGluR1 mRNA levels had returned to control levels, with only a persistent increase in expression unilaterally in the DG (14%). In contrast, an initial down-regulation in mGluR5 mRNA was observed bilaterally in CA4 (-45 and -25%) and CA1 (-46 and -45%), and unilaterally in DG and CA3 (-27 and -42% respectively) 24 h after the last kindled seizure. In the 7 and 28 day kindled groups significant alterations in expression of mGluR5 mRNA were still apparent. These data show that the mRNAs for mGluR1 and mGluR5 are differentially regulated by kindling, indicating that the expression of each of these receptors is under independent regulatory control. These perturbations in mRNA expression may contribute to kindling epileptogenesis but are unlikely to account for the maintenance of the kindled state.
Brain Res Mol Brain Res 1996 Dec 31
PMID:Altered expression of group I metabotropic glutamate receptors in the hippocampus of amygdala-kindled rats. 903 24

Subtypes I, II and III of sodium channel alpha-subunit mRNAs were analyzed in adult rat brain areas after kainate-induced seizures. Tissue samples were microdissected from occipital neocortex, CA1 and CA3 hippocampus areas and dentate gyrus. Three reverse transcriptase-polymerase chain reaction (RT-PCR) protocols were undertaken to amplify these mRNAs. Amplification products were then distinguished after digestion by restriction enzymes, electrophoresis separation and densitometric analysis of gel profiles. PCR 1 evidenced the relative percentage of mRNAs I, II and III as well as neonatal II and III subtype isoforms, which resulted from an alternative splicing. PCR 2 and 3 were performed to focus on the neonatal vs. adult ratio in II and III subtypes, respectively. Seizures were shown to induce an increase in both neonatal subtypes, which suggested an alteration at the splicing level. These changes exhibited a peculiar brain regional distribution, the maximal effect being observed in dentate gyrus and hippocampus CA1 area. In situ hybridization experiments, using a digoxigenin-labeled oligonucleotide probe-specific for neonatal II and III mRNAs, confirmed this increase in neonatal mRNA subtypes. These changes were transient, reaching a maximum 6 h after drug injection, then disappearing between 12 and 48 h. They were prevented by a pre-treatment of animals by MK-801, a non-competitive antagonist of NMDA receptors. This work, thus, suggested that KA-induced seizures can be accompanied by transient alteration in the splicing pattern of sodium channel alpha-subunit mRNAs which resulted in an increase in expression of their neonatal isoforms within localized areas of adult rat brain.
Brain Res Mol Brain Res 1997 Mar
PMID:Increase in mRNAs encoding neonatal II and III sodium channel alpha-isoforms during kainate-induced seizures in adult rat hippocampus. 907 59

Seizures have been shown to regulate neurotrophin expression in adult mammalian brain. However, there has been some controversy as to whether seizures affect neurotrophin expression in very immature brain. In the present study, we have examined the effects of seizures induced by pilocarpine following lithium pretreatment or by kainic acid on the expression of brain derived neurotrophic factor (BDNF) mRNA in developing rat brain by in situ hybridization. In adult brain, lithium/pilocarpine treatment resulted in dramatic elevations of hybridization to BDNF cRNA in neocortical and limbic brain structures. In developing brain, lithium/pilocarpine induced elevations of BDNF mRNA in the hippocampus, piriform and entorhinal cortex as early as postnatal day 7 (P7). By P12, the pattern of enhanced expression was similar to that of the adult. Maximal elevations of hybridization were present 2 to 4 h following pilocarpine injection. Electrophysiological recording demonstrated that lithium/pilocarpine treatment resulted in electrographic seizures. Pretreatment with diazepam blocked the seizures as well as the elevation of BDNF mRNA. Kainic acid induced elevations of BDNF mRNA in the CA3 subfield of the hippocampal pyramidal cell layer, but not in other brain areas in pups as young as P7. These data indicate that seizures during the neonatal and early juvenile period of brain development induce elevated BDNF mRNA expression, and that different methods of seizure induction yield different patterns of elevations in hybridization. Furthermore, BDNF may be capable of playing a role in the development of seizure susceptibility in the immature brain.
Brain Res Mol Brain Res 1997 Mar
PMID:Induction of brain derived neurotrophic factor mRNA by seizures in neonatal and juvenile rat brain. 907 63

A recently cloned rat brain cDNA derives from a novel gene, termed dendrin (DEN), expressed exclusively in forebrain structures, particularly in neocortex, olfactory bulb, hippocampus, caudate-putamen, and limbic system. In these structures, the cognate mRNA is present in neuronal cell bodies and their dendrites, whereas near exclusive dendritic localization is observed for the polypeptide product. In the hippocamus, DEN mRNA is highly expressed in the cell laminae and dendritic layers of the dentate gyrus and CA1 field, but expression is markedly reduced in the CA3 and CA4 areas. The predicted primary structure of the hydrophilic, highly basic 653-amino-acid polypeptide does not suggest a function. The restricted expression and dendritic location are compatible with a role for DEN in synaptic plasticity of central neocortical forebrain neurons.
Mol Cell Neurosci 1997
PMID:Prominent dendritic localization in forebrain neurons of a novel mRNA and its product, dendrin. 907 98

The distribution of the dopaminergic D4 receptor in rat brain was studied employing site directed polyclonal antibodies. Antisera were raised in rabbits to two oligopeptides corresponding to amino acids 160-172 of the second extracellular loop (P1) and amino acids 260-273 of the third intracellular loop (P2) of the D4 receptor sequence. Affinity-purified antibodies (anti-P1 and anti-P2) specifically recognized two major bands of 42-45 and 95 kDa in Western blots of denatured preparations of various rat brain areas. Immunocyto-chemistry studies showed that D4 receptor is widely distributed in rat central nervous system (CNS) showing higher labelling in the hippocampus (CA1, CA2, CA3 and dentate gyrus) frontal cortex, entorhinal cortex, caudate putamen, nucleus accumbens, olfactory tubercle, cerebellum, supraoptic nucleus and sustancia nigra pars compacta. In addition, anti-P1 decreased the binding of the antagonist [3H]YM-09151-2 selective for D2, D3 and D4 receptors but did not modify the binding of [3H]raclopride an antagonist selective for D2 and D3, in striatal synaptosomes. Anti-P2 did not modify the binding of these ligands. These results confirm the selectivity of the antibodies towards the D4 receptor and suggest that the binding site for the antagonists might be located at or close to the second extracellular loop of the protein sequence. D4 receptor protein is mainly expressed in plasma membranes and in the peripheral cytoplasm of neurons and is more widely distributed than was originally proposed based on mRNA localization, since it is present both in limbic, diencephalic and motor areas of rat brain.
Brain Res Mol Brain Res 1997 Apr
PMID:Distribution of D4 dopamine receptor in rat brain with sequence-specific antibodies. 910 65


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