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PubMed1993

Taste memory: the role of protein synthesis in gustatory cortex.

Application of the protein synthesis inhibitor anisomycin to the rat gustatory cortex before and during training impairs conditioned taste aversion (CTA) to saccharin. No behavioral impairment is observed if the inhibitor is applied to an adjacent cortical area or to one cortical hemisphere only. The consumption of saccharin and of total fluid, as well as behavioral recognition of saccharin, is not affected. Preexposure of rats to saccharin several days before training markedly inhibits CTA to that taste. Injection of anisomycin to the gustatory cortex immediately prior to the preexposure period attenuates the latent inhibition. These results suggest that protein synthesis in the gustatory cortex is required for normal acquisition of the memory of taste.

Animals↗
PubMed1987

The effects of protein synthesis inhibition on structural changes associated with learning in the chick.

The effect of the protein synthesis inhibitor anisomycin on the structural changes associated with passive avoidance learning in the chick was investigated. Chicks were trained when they were 24 h old by allowing them to peck at a shiny bead coated with either water or the aversive-tasting substance methylanthranilate (MeA). Chicks which peck the MeA-coated bead will on subsequent testing avoid pecking a similar, but water-coated bead. Behavioural testing was carried out 12 h after training and immediately afterwards the chicks were killed and their brains prepared for electron microscopy. A specific region of the forebrain, the intermediate and medial part of the hyperstriatum ventrale (IMHV) was investigated. When the IMHV of the MeA trained chicks was compared with that of water-trained controls structural changes of the synapse were detected. These changes involved a significant increase in the mean length of the postsynaptic density (LPSD) of symmetrical synapses in the left IMHV. Chicks injected with 0.8 mg of anisomycin 30 min before training with a MeA-coated bead showed aversion for the shiny bead when tested 12 h later. Electron microscopic analysis of the IMHV from these amnestic chicks showed no evidence for the change in LPSD demonstrated in the water-injected controls. These results are discussed in relation to the nature of the memory trace induced by training on a passive avoidance task.

Animals↗
PubMed1988

State-dependent recall can be induced by protein synthesis inhibition: behavioural and morphological observations.

The possibility that the amnesia induced by protein synthesis inhibition is state dependent was investigated. Chicks injected with the protein synthesis inhibitor anisomycin and then trained in a single-trial passive avoidance learning task showed no recall for the task when tested 6 h later in the absence of the drug. If, however, the same chicks were subsequently retested 30 min after a second administration of the drug they demonstrated clear recall for the task. Control groups showed that this effect was not the result of the administration of anisomycin per se but was due to state-dependent recall. Quantitative morphological characterisation of synapses in a region of the chick forebrain (the intermediate part of the medial hyperstriatum ventrale (IMHV) previously shown to be involved in passive avoidance learning was performed. The characteristic increase in the length of the postsynaptic density in the left IMHV was only evident in chicks killed after the behavioural test in which they had demonstrated recall. No synaptic changes were observed in chicks in which state-dependent recall had been demonstrated in a previous test but which were killed after a test in which they appeared amnestic. These results suggest that a memory trace may be established even in the absence of protein synthesis but that this trace may not normally be accessible. It is also suggested that the synaptic changes observed following learning may be dependent on some aspect of the recall phenomenon.

Animals↗
PubMed1987

Investigations into the neuropharmacological basis of temporal stages of memory formation in mice trained in an active avoidance task.

The memorial effects of glutamate, LaCl3, ouabain, or anisomycin injection around the time of active avoidance training in mice were assessed in this study. Based on the Gibbs and Ng hypothesis of memory formation in chicks (Biobehav. Rev., 1 [1977] 113-136), it was predicted that these pharmacological agents would not only induce significant amnesia but, more specifically, short duration memory should be selectively impaired by glutamate and LaCl3, intermediate duration memory should be impaired by ouabain, and anisomycin should affect only long-lasting memories. Results of the experiments described below indicate these drugs are potent inhibitors of memory formation in rodents. In addition, LaCl3-induced amnesia was fully prevented by CaCl2. However, the mechanism by which glutamate and ouabain affected memory may not be exactly as described by Gibbs and Ng: gamma-D-glutamylglycine and diphenylhydantoin did not completely prevent glutamate- and ouabain-induced amnesias, respectively. Finally, all amnestic agents induced amnesia that developed within minutes of training, and the time course of development of amnesia for each drug could not be distinguished from one another. These data are discussed in terms of their implications for the Gibbs and Ng model of memory formation.

Animals↗
PubMed1989

Inhibition of protein synthesis in the dentate gyrus, but not the entorhinal cortex, blocks maintenance of long-term potentiation in rats.

We examined whether the critical protein synthesis for maintenance of perforant path long-term potentiation (LTP) takes place in the dentate gyrus or the entorhinal cortex. Field potential recordings were made of responses in the dentate gyrus to stimulation of the perforant path in urethane-anaesthetized rats. Anisomycin (10 micrograms) injected into the dentate gyrus, but not the entorhinal cortex, 1 h prior to tetanization led to nearly complete decay of perforant path LTP of the excitatory postsynaptic potential (EPSP) within 3 h. Intra-dentate injection of neither actinomycin D (a mRNA synthesis inhibitor) nor boiled anisomycin affected LTP maintenance over 6 h. These results suggest that the proteins necessary for the maintenance of LTP over 6 h are synthesized in the dentate gyrus from already existing mRNA without involving protein synthesis in the cell bodies of the afferent fibres.

Action Potentials↗
PubMed1989

Stimulatory effects of protein synthesis inhibitors on the spreading rate of 3T3 cells.

Three protein synthesis inhibitors, puromycin, cycloheximide and anisomycin were found to increase the rate of spreading of Swiss-3T3 cells after 1 h incubation in the presence of low concentrations of serum. Data from experiments with anisomycin suggest that this effect is roughly proportional to the extent of inhibition of protein synthesis.

Animals↗
PubMed1984

Inhibition of brain protein synthesis suppresses the release of prostaglandin E2 in febrile rabbits.

In rabbits the third cerebral ventricle was perfused using a push-pull cannula. Prostaglandin E2 concentration in the perfusate was measured by radioimmunoassay. Prostaglandin concentration rose during fever induced by an intraventricular injection of endogenous pyrogen. Both fever and the increased prostaglandin concentration were suppressed by the intraventricular injection of 100 micrograms of the protein synthesis inhibitor, anisomycin. A possible interpretation of the findings is that anisomycin inhibits the formation of phospholipase A2. If this is true, the implication is that phospholipase A2 has a rapid turnover in brain.

Animals↗
PubMed1984

RNA and protein synthesis inhibitors: effects on sexual behavior in female rats.

Biochemical evidence indicates that many steroid hormone effects on target tissues are mediated via actions on the genome. Studies on the hormonal control of reproductive behavior have demonstrated several effects of RNA or protein synthesis inhibitors on female sexual behavior in rats. In female rats treated with estrogen and progesterone, intracranial application of actinomycin-D (an RNA synthesis inhibitor) can disrupt lordosis responding if the drug is given in conjunction with estrogen, but not with progesterone. Protein synthesis inhibitors (cycloheximide or anisomycin) applied intracranially at the time of estrogen also disrupt lordosis, with anisomycin antagonizing the progesterone-facilitation of lordosis. Possible neural sites of action of these drugs are considered, as are alternative modes of action of these synthesis inhibitors. Whereas the effects of estrogen on lordosis include the synthesis of some, as yet unidentified, proteins, the exact role for protein synthesis in the mediation of progesterone's actions on lordosis remains less certain.

Animals↗
PubMed1992

Inhibitors of protein and RNA synthesis block structural changes that accompany long-term heterosynaptic plasticity in Aplysia.

Synaptic connections between the sensory and motor neurons of Aplysia in culture undergo long-term facilitation in response to serotonin (5-HT) and long-term depression in response to FMRFamide. These long-term functional changes are dependent on the synthesis of macromolecules during the period in which the transmitter is applied and are accompanied by structural changes. There is an increase and a decrease, respectively, in the number of sensory neuron varicosities in response to 5-HT and FMRFamide. To determine whether macromolecular synthesis is also required for the structural changes, we examined in parallel the effects of inhibitors of protein (anisomycin) or RNA (actinomycin D) synthesis on the structural and functional changes. We have found that anisomycin and actinomycin D block both the enduring alterations in varicosity number and the long-lasting changes in synaptic potential. These results indicate that macromolecular synthesis is required for expression of the long-lasting structural changes in the sensory cells and that this synthesis is correlated with the long-term functional modulation of sensorimotor synapses.

Animals↗
PubMed2004

JNK signaling involved in the effects of cyclic AMP on IL-1beta plus IFNgamma-induced inducible nitric oxide synthase expression in hepatocytes.

cAMP significantly inhibits IL-1beta+IFNgamma-induced iNOS gene expression in hepatocytes, but the signaling pathways responsible for the effect are not known. PKA inhibitors, H89, PKI, and KT5720, had no effect on the recovery of the inhibitory effects of cAMP on cytokine-induced hepatocyte iNOS expression and activity. The JNK inhibitor, SP 600125, effectively reversed the inhibitory effects of cAMP on iNOS expression and significantly increased iNOS promoter activity. A cAMP analogue, dbcAMP, significantly induced JNK signaling and increased AP-1 binding activity in hepatocytes. The JNK activator, anisomycin, inhibited iNOS expression and transcription in hepatocytes as well as AP-1 binding activity; and SP600125 reversed this effect of anisomycin. Overexpression of c-Jun in hepatocytes inhibited IL-1beta+IFNgamma-induced nitrite accumulation and iNOS promoter activity while dominant negative c-Jun partially reversed the inhibitory effects of cAMP on nitrite accumulation. We conclude that JNK signaling plays an important role in the inhibitory effects of cAMP on IL-1beta+IFNgamma-induced iNOS gene expression in cultured hepatocytes.

Animals↗
PubMed2005

Schistosoma mansoni excretory-secretory products stimulate a p38 signalling pathway in Biomphalaria glabrata embryonic cells.

Following infection with Schistosoma mansoni larvae, haemocytes of resistant Biomphalaria glabrata snails execute a rapid defence during which they migrate towards and encapsulate the parasites. Such immediate and precise responses are thought to depend on signal transduction cascades though the signalling components involved remain largely unknown. It is proposed that mitogen-activated protein kinases may play a role in B. glabrata immune signalling, in particular p38 mitogen-activated protein kinases, which are known to be associated with stress and inflammatory signalling. Using degenerate PCR followed by Rapid Amplification of cDNA Ends a full-length p38 mitogen-activated protein kinase-like cDNA was cloned from both the B. glabrata embryonic (Bge) cell line (Bge-p38) and haemocytes (Bgh-p38). In addition, B. glabrata p38 mitogen-activated protein kinase activation was examined at the protein level in Western blot analyses using an antibody that specifically recognises activated/diphosphorylated p38 mitogen-activated protein kinase. Results showed that Bge cell p38 mitogen-activated protein kinase was activated/phosphorylated following 30 min incubation with anisomycin, an established p38 mitogen-activated protein kinase activator. Furthermore, p38 mitogen-activated protein kinase was also activated after only 5 min exposure to either the beta-glucan polymer laminarin or S. mansoni larval excretory-secretory products. In a comparative study, activated haemocyte p38 mitogen-activated protein kinase could also be detected using the anti-phosphorylated p38 antibody following cell treatment with anisomycin. However, in contrast with Bge cells, haemocyte p38 was not activated by either excretory-secretory products or laminarin treatments, suggesting fundamental differences in the role of p38 mitogen-activated protein kinase in signal transduction pathways between haemocytes and Bge cells.

Amino Acid Sequence↗
PubMed2000

Identification of the opioid receptors involved in passive-avoidance learning in the day-old chick during the second wave of neuronal activity.

Long-term memory formation for passive-avoidance learning in the day-old chick is known to have two distinct time windows of protein synthesis (F.M. Freeman, S.P.R. Rose, A.B. Scholey, 1995. Two time windows of anisomycin-induced amnesia for passive-avoidance training in the day-old chick. Neurobiol. Learn. Mem. 63, 291-295). The lobus parolfactorius (LPO) is thought to be an important site for the second wave of protein synthesis which occurs 4-5 h after training. Birds received bilateral intracranial injections of agonists and antagonists for the mu-, delta-, kappa-opioid receptors and the opioid receptor-like (ORL(1)) receptor directly into the LPO at 5 h post-training and were tested for recall 24 h later. Also, 100 microM beta-funaltrexamine (beta-FAN), a mu-opioid receptor antagonist, significantly impaired memory formation (P<0.01). The delta-opioid receptor was also involved in memory formation at this time-point since antagonism of this receptor by 1 mM ICI-174,864 caused amnesia (P<0.01) which was reversed by the agonist, DPLPE. The kappa-opioid receptor appeared not to be involved during the second phase of neuronal activity since neither stimulation by dynorphin nor inhibition by nor-BIN caused amnesia for the task. The ORL(1) receptor agonist orphanin FQ also had no effect suggesting that this receptor was not involved at this 5-h time-point. Cytosolic and mitochondrial protein synthesis has been shown to be important in passive-avoidance learning in the day-old chick. Both chloramphenicol (CAP) and anisomycin (ANI), inhibitors of mitochondrial and cytosolic protein synthesis, respectively, caused disruption when injected 5 h post-training into the LPO (P<0.05). Endomorphin-2 (Endo-2), a mu-opioid receptor agonist, reversed both the ANI- and CAP-sensitivity. However, DPLPE, a delta-opioid receptor agonist, only reversed the effect due to CAP. Possible mechanisms for these effects are discussed.

Age Factors↗
PubMed2001

Stimulation of p38 MAP kinase reduces acidosis and Na(+) overload in preconditioned hepatocytes.

Ischemic preconditioning has been shown to improve liver resistance to hypoxia/reperfusion damage. A signal pathway involving A(2A)-adenosine receptor, G(i)-proteins, protein kinase C and p38 MAP kinase is responsible for the development of hypoxic preconditioning in hepatocytes. However, the coupling of this signal pathway with the mechanisms responsible for cytoprotection is still unknown. We have observed that stimulation of A(2A)-adenosine receptors or of p38 MAPK by CGS21680 or anisomycin, respectively, appreciably reduced intracellular acidosis and Na(+) accumulation developing during hypoxia. These effects were reverted by p38 MAPK inhibitor SB203580 as well as by blocking vacuolar proton ATPase with bafilomycin A(1). SB203580 and bafilomycin A(1) also abolished the cytoprotective action exerted by both CGS21680 and anisomycin. We propose that the stimulation of p38 MAPK by preconditioning might increase hepatocyte resistance to hypoxia by activating proton extrusion through vacuolar proton ATPase, thus limiting Na(+) overload promoted by Na(+)-dependent acid buffering systems.

Acidosis↗
PubMed2003

Structures of five antibiotics bound at the peptidyl transferase center of the large ribosomal subunit.

Structures of anisomycin, chloramphenicol, sparsomycin, blasticidin S, and virginiamycin M bound to the large ribosomal subunit of Haloarcula marismortui have been determined at 3.0A resolution. Most of these antibiotics bind to sites that overlap those of either peptidyl-tRNA or aminoacyl-tRNA, consistent with their functioning as competitive inhibitors of peptide bond formation. Two hydrophobic crevices, one at the peptidyl transferase center and the other at the entrance to the peptide exit tunnel play roles in binding these antibiotics. Midway between these crevices, nucleotide A2103 of H.marismortui (2062 Escherichia coli) varies in its conformation and thereby contacts antibiotics bound at either crevice. The aromatic ring of anisomycin binds to the active-site hydrophobic crevice, as does the aromatic ring of puromycin, while the aromatic ring of chloramphenicol binds to the exit tunnel hydrophobic crevice. Sparsomycin contacts primarily a P-site bound substrate, but also extends into the active-site hydrophobic crevice. Virginiamycin M occupies portions of both the A and P-site, and induces a conformational change in the ribosome. Blasticidin S base-pairs with the P-loop and thereby mimics C74 and C75 of a P-site bound tRNA.

Anisomycin↗
PubMed2003

Discriminative taste aversion learning: a learning task for older chickens.

The study of learning and memory using the chicken model has relied on three learning paradigms, passive avoidance learning, imprinting and the pebble floor task. Passive avoidance learning and imprinting have been used predominantly in very young chickens and cannot be used to access learning and memory in older chickens. We have established a new behavioural learning paradigm, Discriminative Taste Aversion Learning (DTAL), that can be used with both young and older animals. The task requires chickens to discriminate between food crumbs dyed either red or yellow with one colour being associated with the aversive tasting substance, methylanthranilate. Learning can be tested at various times after the training session by presenting chickens with the coloured food crumbs without an aversive taste. Both chickens tested at 5 and 15 days post-hatch learned to avoid the aversive crumbs. Furthermore, the protein synthesis inhibitor anisomycin (30 mM; 10 microl per hemisphere) injected into the intermediate medial hyperstriatum ventrale 15 min pre-training or 45 min post-training blocked long-term memory for the DTAL task when tested 24 h later. Memory for the task was unaffected by anisomycin injection 120 min post-training or in control animals injected with saline at similar times. The timing of the cellular processes of protein synthesis needed for consolidation of the DTAL appears to be similar to those described for the other behavioural paradigms in young chickens.

Age Factors↗
PubMed1990

Ribosome subunit to polysome ratios affect the synthesis of rRNA in Drosophila cells.

Many investigations have revealed that ribosome numbers increase in parallel with the growth rate of cells. Here we show that the absolute level of protein synthesis may not be the only factor influencing rRNA synthesis in a nondividing eukaryotic cell. Under conditions of complete (greater than 99%) inhibition of protein synthesis by four different antibiotics, there is a corresponding inhibition of rRNA synthesis. At lower levels of inhibition of protein synthesis (70%), a different effect of individual antibiotics on rRNA synthesis is observed. Cycloheximide and anisomycin, which cause a decrease in the free subunit pool due to a buildup of polysomes, stimulate rRNA synthesis, whereas puromycin and pactamycin, which cause an increase in the free subunit pool, cause a decrease in rRNA synthesis. These effects on rRNA synthesis are not solely due to a low level of completed proteins. Pactamycin treatment allows completed proteins to be made yet lowers rRNA labeling, while anisomycin treatment does not show synthesis of complete proteins yet increases rRNA labeling. The result suggest that eukaryotic cells may regulate ribosome synthesis in response to the number of free versus translating (polysomal) ribosomes as do Escherichia coli cells.

Animals↗
PubMed2000

Acute modulation of the extent of apoB mRNA editing and the relative rates of syntheses of apoB48 and apoB100 in cultured rat hepatocytes by osmotic and other stress stimuli.

The mRNA for apolipoprotein B (apoB) is edited by the enzyme APOBEC-1, which acts as part of a multiprotein complex or editosome. In cultured rat hepatocytes obtained from fed animals this results in the presence of edited and unedited apoB mRNA in a ratio of approximately 3:2 in the basal state. In this study we show that hyper-osmotic media, which induce cell shrinkage, resulted in an acute increase in the degree of editing of apoB mRNA (hypo-osmotic conditions had no effect). This increase was accompanied by a parallel and highly positively correlated change in the ratio of the rate of synthesis of apoB48 relative to that of apoB100. These changes occurred in the absence of any changes in the overall APOBEC-1 mRNA levels, indicating that the activation of editing occurred at a post-transcriptional level. Levels of total apoB mRNA were also unaffected by hyper-osmotic exposure of the cells indicating that changes in the relative rates of synthesis of apoB48 and apoB100 were due to post/translational events. Exposure of cells to anisomycin at concentrations (50 micrograms/ml) that inhibit protein synthesis or to the transcriptional inhibitor actinomycin D produced changes in the degree of apoB mRNA editing that were similar to those given by hyper-osmotic shock indicating that editing is able to respond acutely to transcriptional or translational inhibition. Anisomycin, at concentrations (50 ng/ml) that activate SAPK/JNK but do not inhibit protein synthesis, gave only a fraction of the effect of hyper-osmotic shock. SB203580, an inhibitor of p38 kinase, did not attenuate the effects of hyper-osmotic conditions on APOBEC-1 editing. These observations suggest that these MAPkinase pathways play a relatively minor part in the transduction of the osmotic stimulus to the editing mechanism. The hyper-osmotically-induced increase in apoB mRNA editing was also insensitive to PD98059 and wortmannin (inhibitors of MEK and PI3 kinase, respectively). These data provide evidence that apoB mRNA editing is capable of acute modulation independently of transcriptional or translational mechanisms and suggest that one or more components of the editosome may undergo post-translational activation.

APOBEC-1 Deaminase↗
PubMed2000

The human papillomavirus type 16 E5 protein modulates ERK1/2 and p38 MAP kinase activation by an EGFR-independent process in stressed human keratinocytes.

The human papillomavirus type 16 E5 gene product has been shown to upregulate the activation of MAP kinases ERK1/2 and cellular proliferation promoted by EGF in a ligand-dependent process. We now report the growth factor-independent modulation of MAP kinases by HPV 16 E5 in human keratinocytes. After treatment with 600 mM sorbitol or low concentrations of anisomycin, E5-expressing cells upregulate the activation of ERK1/2. In addition, E5 enhances p38 activation after anisomycin but not after sorbitol treatment, but it has no effect on MAP kinases activation after shocking the cells with 300 mM sodium chloride. The E5-mediated, sorbitol-dependent increase in ERK1/2 activation is EGF-independent and is only partially inhibited by tyrphostin AG1478, which is known to inhibit specifically EGF receptor activation.

Anisomycin↗