Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of chronic administration of antidepressants on cyclic AMP-dependent protein kinase activity was examined in rat frontal cortex. Chronic administration of imipramine, tranylcypromine, or electroconvulsive seizures decreased cyclic AMP-dependent protein kinase activity in soluble fractions by approximately 25%, whereas enzyme activity was increased in the particulate fractions by approximately 20%. In contrast, enzyme activity in crude homogenates was not altered. This effect appears to be specific to antidepressant drugs, because representatives of several other classes of psychotropic drugs-namely, haloperidol, morphine, and diazepam--failed to alter either soluble or particulate levels of cyclic AMP-dependent protein kinase activity in this brain region following chronic administration. When the total particulate fraction was subfractionated, it was found that chronic imipramine treatment significantly increased the activity of cyclic AMP-dependent protein kinase in crude nuclear fractions but not in crude synaptosomal or microsomal fractions. Taken together, the data raise the possibility that chronic antidepressant treatments may stimulate the translocation of cyclic AMP-dependent protein kinase from the cytosol to the nucleus. This effect would represent a novel action of antidepressants that could contribute to the long-term adaptive changes in brain thought to be essential for the clinical actions of these treatments.
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PMID:Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex. 279 22

A type II calmodulin-dependent protein kinase (CaM kinase II) has been characterized in the synaptic region and may mediate some of the effects of Ca2+ on neuronal excitability. The activity of CaM kinase II is inhibited by anticonvulsant compounds and may be the molecular basis of their neuro-modulatory effects. The direct injection of purified CaM kinase II into invertebrate neurons has demonstrated that this kinase can directly alter specific ion conductances and neuronal activity. A long-lasting decrease in CaM kinase II activity is associated with septal kindling, an experimental model of epilepsy and long-term memory. In summary, CaM kinase II appears to be a central mediator of the effects of Ca2+ on neuronal function. Further investigation of this enzyme and its effects on neuronal activity may provide a molecular insight into an endogenous mechanism for modulating some of the effects of Ca2+ on neuronal excitability and may increase our understanding of the complex regulatory mechanisms that underlie the pathogenesis of seizure discharge and its regulation by anticonvulsant compounds.
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PMID:Molecular mechanisms of neuronal excitability: possible involvement of CaM kinase II in seizure activity. 282 86

Effects of phenytoin (PHT) on the intracellular calcium reservoir, lysosome-like granules (LLG), and calcium-related intracellular events during pentylenetetrazole (PTZ)-induced bursting activity in the neurons of the Japanese land snail, Euhadra peliomphala, were examined. PTZ-induced morphological change of LLG was inhibited by PHT. Calcium release from LLG was inhibited by PHT. PHT also inhibited the cyclic AMP increase by PTZ. PHT inhibited the increase in calcium-dependent protein kinase activity during PTZ-induced bursting activity. These findings suggest that PHT inhibits, as a first step, cyclic AMP increase which is one of the trigger factors of bursting activity as well as subsequent calcium-related intracellular pathological changes during seizure activity.
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PMID:Inhibitory effect of phenytoin on intracellular cyclic nucleotide and calcium changes during pentylenetetrazole-induced bursting activity in snail neurons. 299 18

The synapse is a major regulatory site that has been implicated in modulating neuronal excitability and seizure discharge. Voltage-dependent calcium (Ca2+) entry at the synapse plays a major role in initiating neurotransmitter release and in regulating synaptic function. Thus, obtaining a molecular understanding of the effects of Ca2+ on synaptic modulation would provide important insights into the regulation of synaptic activity and, possibly, the biochemical basis for some forms of epilepsy. Calmodulin is a major Ca2+-binding protein in brain that has been implicated in mediating many of the second messenger effects of Ca2+ on neuronal function. The evidence implicating calmodulin in modulating synaptic excitability will be presented. Calmodulin was shown to be present at the synapse in association with synaptic vesicles and in the postsynaptic density. In addition, several calmodulin-regulated synaptic biochemical processes have been identified, including Ca2+- and calmodulin-regulated protein phosphorylation, vesicular neurotransmitter release, vesicle-membrane interactions, and neurotransmitter turnover. These results indicate that calmodulin may play an important role in synaptic modulation and provide a molecular approach to investigating the Ca2+ signal in brain. Several anticonvulsants have been shown to regulate some of calcium's effects on neuronal function. These anticonvulsants include phenytoin, carbamazepine, and the benzodiazepines. All of these compounds are effective against maximal electric shock (MES) seizure models in animals. Anticonvulsants were tested on several of the Ca2+-calmodulin-regulated synaptic biochemical systems. The results demonstrate that phenytoin, carbamazepine, and the benzodiazepines were effective in inhibiting calcium calmodulin protein kinase activity in membrane and purified kinase preparations, vesicle neurotransmitter release, vesicle-membrane interactions, and voltage-sensitive calcium uptake in intact synaptosomes. Phenobarbital, ethosuximide, trimethadione, valproic acid, and vinyl gamma-aminobutyric acid (GABA) were not effective in inhibiting these calcium-regulated processes. Thus, the effects of anticonvulsants on calcium-regulated processes were selective to a group of anticonvulsants that had been shown in several electrophysiological systems to antagonize some of the actions of calcium on neuronal excitability. These observations suggested the existence of specific membrane receptors that might mediate the effects of these anticonvulsants on neuronal function through the regulation of calcium-calmodulin-regulated processes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A molecular approach to the calcium signal in brain: relationship to synaptic modulation and seizure discharge. 301 Jun 80

To elucidate the intracellular mechanism of the bursting activity which is characteristic of seizure discharge, the behavior of the intracellular cyclic nucleotide and the intracellular calcium during pentylenetetrazole (PTZ)-induced bursting activity in snail neurons was investigated. Cyclic AMP was increased about 3-fold by the incubation of ganglia with PTZ. The effect of PTZ on phosphodiesterase activity measured using either cyclic AMP or cyclic GMP as substrate showed a slight increase in cyclic AMP phosphodiesterase activity. The release of calcium from the lysosome fraction was increased by the incubation of ganglia with dibutyryl cyclic AMP. Protein kinase activity was stimulated by the incubation of ganglia with PTZ. Adenylate cyclase activity was stimulated by the incubation of ganglia with PTZ. These findings suggest that PTZ-induced bursting activity in snail neurons is initiated by an intracellular increase of cyclic AMP, which promotes calcium release from lysosomes and induces protein kinase activation.
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PMID:Behavior of intracellular cyclic nucleotide and calcium in pentylenetetrazole-induced bursting activity in snail neurons. 630 20

The single-locus mutant mouse tottering (tg) displays spontaneous seizures that resemble those in human petit-mal epilepsy. In order to examine alterations in GABAA receptor function which could arise as a result of this mutation, the influx of 36Cl- was determined using microsacs (membrane vesicles) isolated from the brain of tg/tg and coisogenic C57BL/6J (+/+) control mice. In microsacs from both tg/tg and +/+ strains, the maximum level of 36Cl- uptake induced by 50 microM GABA was observed during five seconds of incubation at 28 degrees C. Compared to +/+, the GABA-dependent 36Cl- uptake in tg/tg microsacs was significantly lower and faded rapidly during longer incubations. The levels of gated 36Cl- uptake in tg/tg microsacs were 45 +/- 6.3%, 65 +/- 9.9%, and 33 +/- 6.1% of control (+/+) values for 3-, 5-, and 10-s incubations, respectively. GABAA receptor-specific agonists (30 microM), muscimol, isoguvacine and THIP (4,5,6,7-tetrahydroisoazolo-[5,4-c]pyridin-3-ol) induced 36Cl- influx in the order muscimol > GABA > isoguvacine > THIP. This order was similar for both strains, but the agonist-dependent influx was always significantly lower in tg/tg compared to +/+. Treatment of the microsacs with 10 microM H-89, a membrane-permeant inhibitor of the cAMP-dependent protein kinase (protein kinase A, PKA), was without effect on GABA-gated 36Cl- uptake in +/+, but increased the gated uptake in tg/tg microsacs by 44 +/- 16%. PKA was assayed using [gamma-32]ATP and kemptide as the substrate. Triton X-100 (0.1%) increased both the basal and 8-Br-cAMP dependent PKA activity in microsacs by 3-4 four fold, showing that most of the enzyme was intravesicular. In the presence of Triton, the basal activity of PKA in the tg/tg preparations was twice that of +/+, while the strain difference was no longer apparent in assays containing 8-Br-cAMP. The data suggest that an abnormal elevation of protein kinase A activity in tottering mouse brain contributes to an impairment of GABAA receptor function. It is suggested that the resulting loss of inhibition could play a role in induction of the seizures which characterize the mutant phenotype.
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PMID:Reduced function of gamma-aminobutyric acidA receptors in tottering mouse brain: role of cAMP-dependent protein kinase. 856 63

Activity-mediated gene expression is thought to play an important role in many forms of neuronal plasticities. We have used pentylenetetrazol-induced seizure that produces synchronous and sustained neuronal activity as a model to examine the mechanism(s) of gene activation. The transcription factor CREB (Ca2+/cAMP response element-binding protein) is thought to be necessary for long-term memory formation both in invertebrates and vertebrates. When phosphorylated on Ser133 either by cAMP-dependent protein kinase and/or Ca2+/calmodulin-dependent protein kinases, CREB increases transcription of genes containing the CRE (cAMP response element) sequence. Using an antibody that detects Ser133-phosphorylated CREB protein, we show that CREB phosphorylation is maximal between 3 and 8 min after the onset of seizure activity and declines slowly both in the hippocampus and the cortex. The total amount of CREB protein did not change at the time points examined. The increased phosphorylation of CREB protein is preceded by an increase in the amount of cAMP, suggestive of cAMP-dependent protein kinase activation, in the hippocampus and activation of Ca2+/calmodulin-dependent protein kinases in the cortex. Subsequent to CREB phosphorylation, the expression of the CRE-containing gene, c-fos, and the AP-1 complexes (heterodimers of Fos and Jun family members) is increased. These findings support the role of CREB-mediated gene expression in activity-dependent neuronal plasticities.
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PMID:Neuronal activity increases the phosphorylation of the transcription factor cAMP response element-binding protein (CREB) in rat hippocampus and cortex. 866 77

We have examined the potential involvement of calcium/calmodulin-dependent protein kinases in the regulation of brain-derived neurotrophic factor mRNA in vivo following kainic acid (kainate)-induced seizure activity by in situ hybridization. KN-62, a specific inhibitor of calcium/calmodulin-dependent protein kinase type II and IV, blocked the characteristic induction of brain-derived neurotrophic factor mRNA seen following seizure activity. This blockade was specific to calcium/calmodulin-dependent protein kinase type II and IV as inhibitors of both protein kinase C and cAMP-dependent protein kinase had no effect. Inhibition of brain-derived neurotrophic factor mRNA increases varied between brain regions; an almost complete inhibition was seen throughout cortical regions, whereas only partial inhibitory effects were noted within hippocampus. A similar inhibition of increased c-fos mRNA was observed throughout cortical, hippocampal and diencephalic regions. The two predominant brain-derived neurotrophic factor transcripts induced by kainate, containing exons I or III, were differentially affected by KN-62. The cortical induction of exon I was blocked by KN-62, whereas exon III was not, providing additional evidence for the differential regulation of individual brain-derived neurotrophic factor transcripts and demonstrating that inhibition of brain-derived neurotrophic factor induction was not due to general blockade of seizure activity throughout the neocortex. These data implicate calcium/calmodulin-dependent protein kinase type II or IV in the regulation of brain-derived neurotrophic factor mRNA in vivo and suggest regionally specific mechanisms occur throughout the brain.
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PMID:Attenuation of the seizure-induced expression of BDNF mRNA in adult rat brain by an inhibitor of calcium/calmodulin-dependent protein kinases. 975 46

Membrane depolarization of neurons is thought to lead to changes in gene expression that modulate neuronal plasticity. We used representational difference analysis to identify a group of cDNAs that are induced by membrane depolarization or by forskolin, but not by neurotrophins or growth factors, in PC12 pheochromocytoma cells. One of these genes, SIK (salt-inducible kinase), is a member of the sucrose-nonfermenting 1 protein kinase/AMP-activated protein kinase protein kinase family that was also recently identified from the adrenal gland of rats treated with high-salt diets. SIK mRNA is induced up to eightfold in specific regions of the hippocampus and cortex in rats, following systemic kainic acid administration and seizure induction.
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PMID:The salt-inducible kinase, SIK, is induced by depolarization in brain. 1082 Jan 82

Previous work has shown that seizure-like activity can disrupt the induction of long-term potentiation (LTP). However, how seizure-like event disrupts the LTP induction remains unknown. To understand the cellular and molecular mechanisms underlying this process better, a set of studies was implemented in area CA1 of rat hippocampal slices using extracellular recording methods. We showed here that prior transient seizure-like activity generated by perfused slices with Mg(2+)-free artificial cerebrospinal fluid (ACSF) exhibited a persistent suppression of LTP induction. This effect lasted between 2 and 3 h after normal ACSF replacement and was specifically inhibited by N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphovaleric acid (D-APV) and L-type voltage-operated Ca(2+) channel (VOCC) blocker nimodipine, but not by non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). In addition, this suppressive effect was specifically blocked by the selective protein kinase C (PKC) inhibitor NPC-15437. However, neither Ca(2+)/calmodulin-dependent protein kinase II inhibitor KN-62 nor cAMP-dependent protein kinase inhibitor Rp-adenosine 3', 5'-cyclic monophosphothioate (Rp-cAMPS) affected this suppressive effect. This persistent suppression of LTP was not secondary to the long-lasting changes in NMDA receptor activation, because the isolated NMDA receptor-mediated responses did not show a long-term enhancement in response to a 30-min Mg(2+)-free ACSF application. Additionally, in prior Mg(2+)-free ACSF-treated slices, the entire frequency-response curve of LTP and long-term depression (LTD) is shifted systematically to favor LTD. These results suggest that the increase of Ca(2+) influx through NMDA channels and L-type VOCCs in turn triggering a PKC-dependent signaling cascade is a possible cellular basis underlying this seizure-like activity-induced inhibition of LTP.
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PMID:Transient removal of extracellular Mg(2+) elicits persistent suppression of LTP at hippocampal CA1 synapses via PKC activation. 1098 2


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