Corticotropin-Releasing Factor Produces a Protein Synthesis–Dependent Long-Lasting Potentiation in Dentate Gyrus Neurons

2000 ◽  
Vol 83 (1) ◽  
pp. 343-349 ◽  
Author(s):  
Hai L. Wang ◽  
Li Y. Tsai ◽  
Eminy H. Y. Lee
Keyword(s):  
Protein Synthesis ◽  
Synaptic Transmission ◽  
Dentate Gyrus ◽  
Late Phase ◽  
Long Term Potentiation ◽  
Corticotropin Releasing Factor ◽  
Rat Hippocampus ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor

Corticotropin-releasing factor (CRF) was shown to produce a long-lasting potentiation of synaptic efficacy in dentate gyrus neurons of the rat hippocampus in vivo. This potentiation was shown to share some similarities with tetanization-induced long-term potentiation (LTP). In the present study, we further examined the mechanism underlying CRF-induced long-lasting potentiation in rat hippocampus in vivo. Results indicated that the RNA synthesis inhibitor actinomycin-D, at a concentration that did not change basal synaptic transmission alone (5 μg), significantly decreased CRF-induced potentiation. Similarly, the protein synthesis inhibitor emetine, at a concentration that did not affect hippocampal synaptic transmission alone (5 μg), also markedly inhibited CRF-induced potentiation. These results suggest that like the late phase of LTP, CRF-induced long-lasting potentiation also critically depend on protein synthesis. Further, prior maximum excitation of dentate gyrus neurons with tetanization occluded further potentiation of these neurons produced by CRF and vise versa. Moreover, quantitative reverse transcription-polymerase chain reaction analysis revealed that CRF mRNA level in the dentate gyrus was significantly increased 1 h after LTP recording. Together with our previous findings that CRF antagonist dose-dependently diminishes tetanization-induced LTP, these results suggest that both CRF-induced long-lasting potentiation and tetanization-induced LTP require protein synthesis and that CRF neurons are possibly involved in the neural circuits underlying LTP.

scholarly journals Neuroligin-3 Regulates Excitatory Synaptic Transmission and EPSP-Spike Coupling in the Dentate Gyrus In Vivo

2021 ◽  
Author(s):  
Julia Muellerleile ◽  
Matej Vnencak ◽  
Angelo Ippolito ◽  
Dilja Krueger-Burg ◽  
Tassilo Jungenitz ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Dentate Gyrus ◽  
Long Term Potentiation ◽  
Autism Spectrum ◽  
Perforant Path ◽  
Adhesion Protein ◽  
Neuronal Excitation ◽  
Term Potentiation

Abstract Neuroligin-3 (Nlgn3), a neuronal adhesion protein implicated in autism spectrum disorder (ASD), is expressed at excitatory and inhibitory postsynapses and hence may regulate neuronal excitation/inhibition balance. To test this hypothesis, we recorded field excitatory postsynaptic potentials (fEPSPs) in the dentate gyrus of Nlgn3 knockout (KO) and wild-type mice. Synaptic transmission evoked by perforant path stimulation was reduced in KO mice, but coupling of the fEPSP to the population spike was increased, suggesting a compensatory change in granule cell excitability. These findings closely resemble those in neuroligin-1 (Nlgn1) KO mice and could be partially explained by the reduction in Nlgn1 levels we observed in hippocampal synaptosomes from Nlgn3 KO mice. However, unlike Nlgn1, Nlgn3 is not necessary for long-term potentiation. We conclude that while Nlgn1 and Nlgn3 have distinct functions, both are required for intact synaptic transmission in the mouse dentate gyrus. Our results indicate that interactions between neuroligins may play an important role in regulating synaptic transmission and that ASD-related neuroligin mutations may also affect the synaptic availability of other neuroligins.

Effect of protein synthesis Inhibition on brain corticotropin-releasing factor and plasma adrenocorticotropin

1990 ◽  
Vol 68 (12) ◽  
pp. 1595-1600
Author(s):  
Daniel A. Haas ◽  
William C. Sturtridge ◽  
Susan R. George
Keyword(s):  
Protein Synthesis ◽  
Corticotropin Releasing Factor ◽  
Protein Synthesis Inhibitor ◽  
Protein Synthesis Inhibition ◽  
Plasma Acth ◽  
Synthesis Inhibitor ◽  
Brain Areas ◽  
Synthesis Inhibition ◽  
General Protein Synthesis ◽  
General Protein

The effect of inhibiting protein synthesis on concentrations of corticotropin-releasing factor (CRF) in rat brain and plasma adrenocorticotropin (ACTH) was assessed following the administration of the general protein synthesis inhibitor anisomycin. Compared with vehicle-injected controls, protein synthesis inhibition resulted in significantly reduced CRF immunoreactivity (CRF-ir) in median eminence within 1 h (p < 0.01), remained decreased after 4 h (p < 0.025), and was nonsignificantly decreased after 24 h. Plasma ACTH levels were greatly increased within 1 h posttreatment (p < 0.0005), continued elevated after 4 h (p < 0.01), and returned to normal levels after 24 h. CRF-ir measured in other brain areas 24 h after anisomycin showed decreased levels in medulla–pons (p < 0.025) and neurointermediate lobe of pituitary (p < 0.05), with no change noted in frontal cortex, hippocampus, midbrain–thalamus, or cerebellum. Overall these data show that blockade of normal protein synthesis with anisomycin can elicit changes in CRF-ir and ACTH content.Key words: corticotropin-releasing factor, adrenocorticotropin, anisomycin.

scholarly journals Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase

2016 ◽  
Vol 60 (10) ◽  
pp. 6271-6280 ◽  
Author(s):  
Andrés Palencia ◽  
Xianfeng Li ◽  
Wei Bu ◽  
Wai Choi ◽  
Charles Z. Ding ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Mycobacterium Tuberculosis ◽  
Cell Activity ◽  
Trna Synthetase ◽  
Protein Synthesis Inhibitor ◽  
Drug Resistant ◽  
Protein Synthesis Inhibitors ◽  
Synthesis Inhibitor ◽  
Content Type

ABSTRACTThe recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains ofMycobacterium tuberculosishighlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective againstM. tuberculosisin TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), toM. tuberculosisLeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity againstM. tuberculosis. Importantly, their good oral bioavailability translates intoin vivoefficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.

scholarly journals Long-Lasting Effects of GABA Infusion Into the Cerebral Cortex of the Rat

2000 ◽  
Vol 7 (1-2) ◽  
pp. 1-8 ◽  
Author(s):  
Teresa Montiel ◽  
Daniel Almeida ◽  
Iván Arango ◽  
Eduardo Calixto ◽  
César Casasola ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Long Term Potentiation ◽  
Information Storage ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor ◽  
Receptor Stimulation ◽  
Paroxysmal Activity ◽  
The Brain

In electrophysiological terms, experimental models of durable information storage in the brain include long-term potentiation (LTP), long-term depression, and kindling. Protein synthesis correlates with these enduring processes. We propose a fourth example of long-lasting information storage in the brain, which we call the GABA-withdrawal syndrome (GWS). In rats, withdrawal of a chronic intracortical infusion of GABA, a ubiquitous inhibitory neurotransmitter, induced epileptogenesis at the infusion site. This overt GWS lasted for days. Anisomycin, a protein synthesis inhibitor, prevented the appearance of GWSin vivo. Hippocampal and neocortical slices showed a similar post-GABA hyperexcitabilityin vitroand an enhanced susceptibility to LTP induction. One to four months after the epileptic behavior disappeared, systemic administration of a subconvulsant dose of pentylenetetrazol produced the reappearance of paroxysmal activity. The long-lasting effects of tonicGABAAreceptor stimulation may be involved in long-term information storage processes at the cortical level, whereas the cessation ofGABAAreceptor stimulation may be involved in chronic pathological conditions, such as epilepsy. Furthermore, we propose that GWS may represent a common key factor in the addiction to GABAergic agents (for example, barbiturates, benzodiazepines, and ethanol). GWS represents a novel form of neurono-glial plasticity. The mechanisms of this phenomenon remain to be understood.

scholarly journals TePhe, a tellurium-containing phenylalanine mimic, allows monitoring of protein synthesis in vivo with mass cytometry

2019 ◽  
Vol 116 (17) ◽  
pp. 8155-8160 ◽  
Author(s):  
Jay Bassan ◽  
Lisa M. Willis ◽  
Ravi N. Vellanki ◽  
Alan Nguyen ◽  
Landon J. Edgar ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Direct Detection ◽  
Aromatic Amino Acids ◽  
Protein Synthesis Inhibitor ◽  
Mass Cytometry ◽  
Synthesis Inhibitor ◽  
Molecular Specificity ◽  
Noncanonical Amino Acid

Protein synthesis is central to maintaining cellular homeostasis and its study is critical to understanding the function and dysfunction of eukaryotic systems. Here we report L-2-tellurienylalanine (TePhe) as a noncanonical amino acid for direct measurement of protein synthesis. TePhe is synthetically accessible, nontoxic, stable under biological conditions, and the tellurium atom allows its direct detection with mass cytometry, without postexperiment labeling. TePhe labeling is competitive with phenylalanine but not other large and aromatic amino acids, demonstrating its molecular specificity as a phenylalanine mimic; labeling is also abrogated in vitro and in vivo by the protein synthesis inhibitor cycloheximide, validating TePhe as a translation reporter. In vivo, imaging mass cytometry with TePhe visualizes translation dynamics in the mouse gut, brain, and tumor. The strong performance of TePhe as a probe for protein synthesis, coupled with the operational simplicity of its use, suggests TePhe could become a broadly applied molecule for measuring translation in vitro and in vivo.

Hypotonicity stimulates renal epithelial sodium transport by activating JNK via receptor tyrosine kinases

2007 ◽  
Vol 293 (1) ◽  
pp. F128-F138 ◽  
Author(s):  
Akiyuki Taruno ◽  
Naomi Niisato ◽  
Yoshinori Marunaka
Keyword(s):  
Protein Synthesis ◽  
Tyrosine Kinase ◽  
P38 Mapk ◽  
Egf Receptor ◽  
Late Phase ◽  
Pi3 Kinase ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor ◽  
Hypotonic Stress ◽  
Stimulation Of

We previously reported that hypotonic stress stimulated transepithelial Na+ transport via a pathway dependent on protein tyrosine kinase (PTK; Niisato N, Van Driessche W, Liu M, Marunaka Y. J Membr Biol 175: 63–77, 2000). However, it is still unknown what type of PTK mediates this stimulation. In the present study, we investigated the role of receptor tyrosine kinase (RTK) in the hypotonic stimulation of Na+ transport. In renal epithelial A6 cells, we observed inhibitory effects of AG1478 [an inhibitor of the EGF receptor (EGFR)] and AG1296 [an inhibitor of the PDGF receptor (PDGFR)] on both the hypotonic stress-induced stimulation of Na+ transport and the hypotonic stress-induced ligand-independent activation of EGFR. We further studied whether hypotonic stress activates members of the MAP kinase family, ERK1/2, p38 MAPK, and JNK/SAPK, via an RTK-dependent pathway. The present study indicates that hypotonic stress induced phosphorylation of ERK1/2 and JNK/SAPK, but not p38 MAPK, that the hypotonic stress-induced phosphorylation of ERK1/2 and JNK/SAPK was diminished by coapplication of AG1478 and AG1296, and that only JNK/SAPK was involved in the hypotonic stimulation of Na+ transport. A further study using cyclohexamide (a protein synthesis inhibitor) suggests that both RTK and JNK/SAPK contributed to the protein synthesis-independent early phase in hypotonic stress-induced Na+ transport, but not to the protein synthesis-dependent late phase. The present study also suggests involvement of phosphatidylinositol 3-kinase (PI3-kinase) in RTK-JNK/SAPK cascade-mediated Na+ transport. These observations indicate that 1) hypotonic stress activates JNK/SAPK via RTKs in a ligand-independent pathway, 2) the RTK-JNK/SAPK cascade acts as a mediator of hypotonic stress for stimulation of Na+ transport, and 3) PI3-kinase is involved in the RTK-JNK/SAPK cascade for the hypotonic stress-induced stimulation of Na+ transport.

scholarly journals Role of lysosomal cathepsin activities in cell hypertrophy induced by NH4Cl in cultured renal proximal tubule cells.

1996 ◽  
Vol 7 (1) ◽  
pp. 73-80
Author(s):  
H Ling ◽  
S Vamvakas ◽  
M Gekle ◽  
L Schaefer ◽  
M Teschner ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cell Protein ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor ◽  
Renal Hypertrophy ◽  
Cytosolic Ph ◽  
Cell Hypertrophy ◽  
Renal Proximal Tubule Cells

An increase of renal ammoniagenesis has been implicated in renal hypertrophy associated with various clinical disorders such as metabolic acidosis, diabetic nephropathy, and renal insufficiency. In vivo and in vitro studies have shown that ammonia promotes hypertrophy in tubular epithelial cells. To elucidate its role on protein turnover, the effects of NH4Cl on the activities of cathepsins B, H, and L+B, as well as on protein synthesis and degradation in LLC-PK1 cells, were investigated. The results show that NH4Cl (20 mM) induced cell hypertrophy, as defined by an increase in both cell protein content and cell volume (+25.5 +/- 1.3 and +10.4 +/- 0.1% after 48 h). This hypertrophy was associated with the suppression of the activities of cathepsins B and L+B (-57.0 +/- 0.9 and -54.5 +/- 1.5% after 48 h) and a reduction of protein degradation rate (-59.7 +/- 4.1% after 48 h), but without enhanced protein synthesis. The findings were further supported with an additional experiment, showing that the protein synthesis inhibitor cycloheximide (10 microM) did not blunt NH4Cl-induced cell hypertrophy. Moreover, NH4Cl (20 mM) resulted in a persistent elevation of the lysosomal pH, whereas the rise in the cytosolic pH was only transient. This alkalinization in lysosomes may be causatively involved in the impairment of the activities of cathepsins B and L+B. In conclusion, the suppression of the activities of cathepsins B and L+B and the subsequent reduction of protein breakdown due to intralysosomal alkalinization contribute to NH4Cl-induced hypertrophy in LLC-PK1 cells.

Altered Plasticity in Hippocampal CA1, But Not Dentate Gyrus, Following Long-Term Environmental Enrichment

2010 ◽  
Vol 103 (6) ◽  
pp. 3320-3329 ◽  
Author(s):  
Michael J. Eckert ◽  
David K. Bilkey ◽  
Wickliffe C. Abraham
Keyword(s):  
Synaptic Transmission ◽  
Dentate Gyrus ◽  
Long Term Potentiation ◽  
Enriched Environment ◽  
Cognitive Improvement ◽  
Stratum Oriens ◽  
Hippocampal Ca1

Exposure to an enriched environment can improve cognitive functioning in normal animals as well as in animal models of neurological disease and impairment. However, the physiological processes that mediate these changes are poorly understood. Previously we and others have found changes in hippocampal synaptic transmission and plasticity after 2–4 wk of enrichment although others have not observed effects. To determine whether long-term enrichment produces more robust changes, we housed rats continuously in an enriched environment for a minimum of 3 mo and then tested for effects on hippocampal physiology in vitro and in vivo. Enriched housing improved spatial learning compared with social and isolated housing, but surprisingly this was not accompanied by changes in basal synaptic transmission in either CA1 or the dentate gyrus as measured either in vitro or in vivo. This lack of change may reflect the operation of homeostatic mechanisms that keep global synaptic weights within a narrow range. In tests of synaptic plasticity, the induction of long-term potentiation was not changed in either CA1 or the dentate gyrus. However, in CA1 of enriched rats, there was less long-term depression in stratum radiatum, less depotentiation in stratum oriens, and altered paired-pulse inhibition of population spikes evoked in stratum oriens. These effects suggest that there are altered synaptic and network dynamics in hippocampal CA1 that contribute to the enrichment-related cognitive improvement.

scholarly journals Changes in protein synthesis accompanying long-term potentiation in the dentate gyrus in vivo

1993 ◽  
Vol 13 (4) ◽  
pp. 1346-1353 ◽  
Author(s):  
MS Fazeli ◽  
J Corbet ◽  
MJ Dunn ◽  
AC Dolphin ◽  
TV Bliss
Keyword(s):  
Protein Synthesis ◽  
Dentate Gyrus ◽  
Long Term Potentiation ◽  
Term Potentiation

scholarly journals Neuroprotection by Osteopontin in Stroke

2005 ◽  
Vol 25 (2) ◽  
pp. 217-225 ◽  
Author(s):  
Robert Meller ◽  
Susan L Stevens ◽  
Manabu Minami ◽  
Jennifer A Cameron ◽  
Sonya King ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Synthesis ◽  
Protective Effect ◽  
Cortical Neuron ◽  
Neuroprotective Effect ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor ◽  
In Vivo Models

Osteopontin (OPN) is a secreted extracellular phosphoprotein involved in diverse biologic functions, including inflammation, cell migration, and antiapoptotic processes. Here we investigate the neuroprotective potential of OPN to reduce cell death using both in vitro and in vivo models of ischemia. We show that incubation of cortical neuron cultures with OPN protects against cell death from oxygen and glucose deprivation. The effect of OPN depends on the Arg–Gly–Asp (RGD)-containing motif as the protective effect of OPN in vitro was blocked by an RGD-containing hexapeptide, which prevents integrin receptors binding to their ligands. Osteopontin treatment of cortical neuron cultures caused an increase in Akt and p42/p44 MAPK phosphorylation, which is consistent with OPN-inducing neuroprotection via the activation of these protein kinases. Indeed, the protective effect of OPN was reduced by inhibiting the activation of Akt and p42/p44 MAPK using LY294002 and U0126, respectively. The protective effect of OPN was also blocked by the protein synthesis inhibitor cycloheximide, suggesting that the neuroprotective effect of OPN required new protein synthesis. Finally, intracerebral ventricular administration of OPN caused a marked reduction in infarct size after transient middle cerebral artery occlusion in a murine stroke model. These data suggest that OPN is a potent neuroprotectant against ischemic injury.

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