Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: CAS:6893-26-1 (glutamate)
73,096 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients infected with the human immunodeficiency virus (HIV), and other mammals infected with related lentiviruses, exhibit fatigue, altered sleep patterns, and abnormal circadian rhythms. A circadian clock in the hypothalamic suprachiasmatic nucleus (SCN) temporally regulates these functions in mammals. We found that a secretary HIV transcription factor, transactivator of transcription (Tat), resets the murine circadian clock, in vitro and in vivo, at clinically relevant concentrations (EC(50) = 0.31 nM). This effect of Tat occurs only during the subjective night, when N-methyl-D-aspartate (NMDA) receptor [D-2-amino-5-phosphonovaleric acid (0.1 mM)] and nitric oxide synthase (N(G)-nitro-L-arginine methyl ester, 0.1 mM) inhibitors block Tat-induced phase shifts. Whole cell recordings of SCN neurons within the brain slice revealed that Tat did not activate NMDA receptors directly but potentiated NMDA receptor currents through the enhancement of glutamate release. Consistent with this presynaptic mechanism, inhibitors of neurotransmission block Tat-induced phase shifts, such as tetrodotoxin (1 microM), tetanus toxin (1 microM), P/Q/N type-calcium channel blockers (1 microM omega-agatoxin IVA and 1 microM omega-conotoxin GIVA) and bafilomycin A(1) (1 microM). Thus the effect of Tat on the SCN may underlie lentiviral circadian rhythm dysfunction by operating as a disease-dependent modulator of light entrainment through the enhancement of excitatory neurotransmission.
...
PMID:HIV protein, transactivator of transcription, alters circadian rhythms through the light entrainment pathway. 1586 Jun 48

We investigated the effect of type 1 human immunodeficiency virus (HIV-1) regulatory protein Tat on N-methyl-d-aspartate (NMDA) receptors expressed in Xenopus oocytes by voltage-clamp recording and its role in NMDA-mediated neurotoxicity using cultured rat hippocampal neurons. Tat (0.01-1muM) potentiated NMDA-induced currents of recombinant NMDA receptors. However, in the presence of Zn(2+), the potentiating effect of Tat was much more pronounced, indicating an additional Zn(2+)-related effect on NMDA receptors. Consistently, Tat potentiated currents of the particularly Zn(2+)-sensitive NR1/NR2A NMDA receptor with a higher efficacy, whereas currents from a Zn(2+)-insensitive mutant were only marginally augmented. In addition, chemical-modified Tat, deficient for metal binding, did not reverse Zn(2+)-mediated inhibition of NMDA responses, demonstrating that Tat disinhibits NMDA receptors from Zn(2+)-mediated antagonism by complexing the cation. We therefore investigated the interplay of Tat and Zn(2+) in NMDA-mediated neurotoxicity using cultures of rat hippocampal neurons. Zn(2+) exhibited a prominent rescuing effect when added together with the excitotoxicant NMDA, which could be reverted by the Zn(2+)-chelator tricine. Similar to tricine, Tat enhanced NMDA-mediated neurotoxicity in the presence of neuroprotective Zn(2+) concentrations. Double-staining with antibodies against Tat and the NR1 subunit of the NMDA receptor revealed partial colocalization of the immunoreactivities in membrane patches of hippocampal neurons, supporting the idea of a direct interplay between Tat and glutamatergic transmission. We therefore propose that release of Zn(2+)-mediated inhibition of NMDA receptors by HIV-1 Tat contributes to the neurotoxic effect of glutamate and may participate in the pathogenesis of AIDS-associated dementia.
...
PMID:Molecular interactions of the type 1 human immunodeficiency virus transregulatory protein Tat with N-methyl-d-aspartate receptor subunits. 1596 99

Induction of heat shock protein 70 (Hsp70) via sublethal stress protects neurons from subsequent lethal injuries. Here we show that specific and efficient intracellular transduction of Hsp70 can be achieved utilizing an 11 amino acid leading sequence from human immunodeficiency virus (TAT-Hsp70) in primary neuronal cultures. Western blot and immunohistochemistry demonstrated intracellular accumulation of Hsp70 in insoluble protein fractions and mitochondrial compartments. We then examined the effects of Hsp70 overexpression using TAT-Hsp70 in models of nitrosative and excitotoxic neuronal death in vitro. Neurons were pre-incubated with 300 nM TAT-Hsp 70 overnight, then exposed to either peroxynitrite (ONOO-) or glutamate. TAT-Hsp70 maintained cellular respiration, inhibited extracellular lactate dehydrogenase release, and/or reduced cell death assessed by flow cytometry vs. vehicle, wild-type Hsp70, and TAT-beta-galactosidase controls. Hsp70 transduction using a TAT fusion protein is an effective method to selectively increase Hsp70 in neurons and is sufficient to provide neuroprotection from nitrosative stress and excitotoxicity. Further study is needed to confirm whether TAT-Hsp70 is protective in in vivo models of brain injury.
...
PMID:Selectively increasing inducible heat shock protein 70 via TAT-protein transduction protects neurons from nitrosative stress and excitotoxicity. 1599 87

Neurologic decline associated with penetration of human immunodeficiency virus type 1(HIV-1) into the central nervous system is thought to be due, in large part, to inflammation and local secretion of neurotoxic substances. To examine the cellular processes that mediate neurotoxicity in vivo, the authors valuated the ability of neurons to maintain intracellular calcium homeostasis in the presence of toxic cerebrospinal fluid (CSF) (CSF(tox)) collected from a subset of HIV-infected individuals. Exposure of rat neural cultures to CSF(tox) resulted in a gradual increase in intracellular calcium in neurons (+63%), microglia (+251%), and astrocytes (+52%). Pretreatment of neural cultures with CSF(tox) resulted in an exaggerated calcium response to a brief pulse of glutamate and a > 90% suppression of the rate of recovery of intracellular calcium. Attempts to model the deficit using inhibitors of calcium transport across endoplasmic reticulum, mitochondrial, or plasma membrane indicated that blockade of the plasma membrane sodium/calcium exchanger was best able to reproduce the deficits seen during exposure to CSF(tox). Because the inability of cells to maintain calcium homeostasis would lead to exaggerated responses from a wide variety of stimuli, therapeutics designed to facilitate calcium transport from the cell may provide more comprehensive and effective intervention than strategies targeted to specific receptor pathways.
...
PMID:Cerebrospinal fluid from human immunodeficiency virus--infected individuals facilitates neurotoxicity by suppressing intracellular calcium recovery. 1603 93

Certain viruses can infect neurons and cause persistent infections with restricted expression of viral proteins. To study the consequences of such viral proteins on synaptic functions, the effects of two influenza A virus proteins, the nonstructural protein 1 (NS1) and the nucleoprotein (NP), were analyzed in cultures of rat hippocampal neurons. Transduction of the NS1 and NP proteins into the neurons was performed by applying the 11-amino acid peptide transduction domain (PTD) of human immunodeficiency virus (HIV) TAT coupled to the viral proteins. Neurons exposed to the NS1 and NP fusion proteins (NS1-PTD and NP-PTD, respectively) for 4 h were immunopositive for these proteins as diffuse cytoplasmic and nuclear distribution. After exposure for 48 h to NP-PTD, a punctate pattern of the immunolabel appeared in dendritic spinelike processes. Electrophysiologically, a reduction in both the frequency of spontaneous excitatory synaptic activity and in the amplitude of the miniature excitatory postsynaptic currents were recorded after exposing the hippocampal neurons to NP-PTD between 17 and 22 days in culture. These changes may reflect disturbances in postsynaptic functions. No such alterations in synaptic activities were recorded after exposure to NS1-PTD or to green fluorescent protein-PTD, which was used as a control. Based on these findings the authors hypothesize that the viral NP, by its localization to dendritic spinelike structures, interferes with the expression or anchoring of postsynaptic glutamate receptors and thereby disturbs synaptic functions. Thus a persistent viral infection in the brain may be associated with functional disturbances at the synaptic level.
...
PMID:Effects on synaptic activity in cultured hippocampal neurons by influenza A viral proteins. 1616 82

Human immunodeficiency virus (HIV)-associated dementia (HAD) is a frequent complication in HIV+ subjects. Several electrophysiological markers and motor control are altered in HIV+ subjects, including event-related potentials (N2-P3 changes). These are electrophysiological indicators of cognitive processing. The mechanisms by which HIV induces neurophysiological abnormality is still under research. However, several neurotransmitters have been implicated. For example, glutamate and the vasoactive intestinal neuropeptide (VIP). In this study, we support further this notion indicating that HIVgp120, a glycoprotein derived from HIV, is involved in the pathogenesis of neuropsychiatric abnormalities. We also have observations suggesting that one HIVgp120 mechanism of action is to interfere with cholinergic neurotransmission. Our results indicate that event-related potentials (ERP) were affected by HIVgp120, in particular N2 and P3. In addition, motor coordination was severely affected. Both parameters were maintained near normality when rats were simultaneously treated with nicotine. These results support further an HIVgp120-caused alteration of cholinergic neurotransmission that might be part of the etiology of neuropsychiatric disturbances.
...
PMID:Nicotine prevents HIVgp120-caused electrophysiological and motor disturbances in rats. 1626 13

We investigated the effects of the human immunodeficiency virus-1 transactivator of transcription (Tat) on the release of norepinephrine (NE) from human and rat brain synaptosomes. Tat could not evoke directly release of [3H]NE. In the presence of Tat (1 nM), N-methyl-D-aspartate (NMDA) concentrations unable to release (human synaptosomes) or slightly releasing (rat synaptosomes) [3H]NE became very effective. The NMDA/Tat-evoked release depends on NMDA receptors (NMDARs) since it was abolished by MK-801 (dizocilpine). Tat binding at NMDARs was excluded. The NMDA-induced release of [3H]NE in the presence of glycine was further potentiated by Tat. The release evoked by NMDA/glycine/Tat depends on metabotropic glutamate receptor 1 (mGluR1) activation, since it was halved by mGluR1 antagonists. Tat seems to act at the glutamate recognition site of mGluR1. Recently, Tat was shown to release [3H]acetylcholine from human cholinergic terminals; here, we demonstrate that this effect is also mediated by presynaptic mGluR1. The peptide sequence Tat41-60, but not Tat61-80, mimicked Tat. Phospholipase C, protein kinase C, and cytosolic tyrosine kinase are involved in the NMDA/glycine/Tat-evoked [3H]NE release. To conclude, Tat can represent a potent pathological agonist at mGlu1 receptors able to release acetylcholine from human cholinergic terminals and up-regulate NMDARs mediating NE release from human and rat noradrenergic terminals.
...
PMID:The human immunodeficiency virus-1 protein transactivator of transcription up-regulates N-methyl-D-aspartate receptor function by acting at metabotropic glutamate receptor 1 receptors coexisting on human and rat brain noradrenergic neurones. 1648 29

Central nervous system disorders are still a common complication of human immunodeficiency virus (HIV) infection and can lead to dementia and death. They are mostly the consequences of an inflammatory macrophagic activation and relate to glutamate-mediated excitotoxicity. However, recent studies also suggest neuroprotective aspects of macrophage activation through the expression of glutamate transporters and glutamine synthetase. We thus aimed to study whether HIV infection or activation of macrophages could modulate glutamate metabolism in these cells. We assessed the effect of HIV infection on glutamate transporter expression as well as on glutamate uptake by macrophages and showed that glutamate transport was partially decreased in the course of virus replication, whereas excitatory amino acid transporter-2 (EAAT-2) gene expression was dramatically increased. The consequences of HIV infection on glutamine synthetase were also measured and for the first time we show the functional expression of this key enzyme in macrophages. This expression was repressed during virus production. We then quantified EAAT-1 and EAAT-2 gene expression as well as glutamate uptake in differentially activated macrophages and show that the effects of HIV are not directly related to pro- or anti-inflammatory mediators. Finally, this study shows that glutamate transport by macrophages is less affected than what has been described in astrocytes. Macrophages may thus play a role in neuroprotection against glutamate in the infected brain, through their expression of both EAATs and glutamine synthetase. Because glutamate metabolism by activated macrophages is sensitive to both HIV infection and inflammation, it may thus be of potential interest as a therapeutic target in HIV encephalitis.
...
PMID:Glutamate metabolism in HIV-infected macrophages: implications for the CNS. 1668 72

The ability of feline immunodeficiency virus (FIV) to induce neurodegenerative changes in vitro similar to those due to HIV was examined as a potential model to examine the mechanisms underlying AIDS dementia. Primary cultures of feline neural tissue (neurons, astrocytes and microglia) were established from E40-E57 fetal cat cortex and challenged by inoculation with the NCSU₁ strain of FIV. Proviral FIV was detected in the cultures and correlated with the presence of microglia. No direct toxicity of FIV was seen. Stimulation of FIV-inoculated cortical cultures with 20 uM glutamate resulted in a greatly enhanced acute swelling response in approximately 14-24% of the neurons and an increase in the number of dead cells after 24 h relative to control cultures. The enhanced responses were due to an increase in the sensitivity of the cells to glutamate and were dependent on the presence of a soluble factor in the medium. The similarity of the indirect excitoxic effects of FIV to current models of HIV-gp120 neurotoxicity and the versatility of the in vitro cultures, indicate that FIV should provide a valuable model for the investigation of the mechanisms of neurodegeneration in AIDS dementia.
...
PMID:Enhanced Excitotoxicity in Primary Feline Neural Cultures Exposed to Feline Immunodeficiency Virus (FIV). 1687 68

Structural data support a model where - following proteolytic cleavage--the amino-terminal domain of human immunodeficiency virus type 1 (HIV-1) capsid protein refolds into a beta-hairpin/helix tertiary structure that is stabilized by a buried salt bridge forming between the positively charged primary imino group of a proline residue and the negatively charged carboxyl group of a conserved aspartate. In order to evaluate the contribution of either side-chain length or charge to the formation of infectious virus capsids, aspartate 183 was substituted for glutamate or asparagine in the viral context. It was found that both modifications abolished infectivity of the corresponding viruses in permissive T lymphocytes, although none of particle assembly and release, RNA encapsidation, incorporation of Env glycoproteins and packaging of cyclophilin A were impaired. However, whereas biophysical analyses of mutant virions yielded wild-type-like particle sizes and densities, electron microscopy revealed aberrant core morphologies that could be attributed to either increased (D183N) or reduced (D183E) capsid stability. Although the two amino acid substitutions had opposing effects upon core stability, both mutants were shown to exhibit a severe block in early reverse transcription, underscoring the importance of correct salt-bridge formation for early steps of virus replication.
...
PMID:Capsid stability and replication of human immunodeficiency virus type 1 are influenced critically by charge and size of Gag residue 183. 1717 Apr 53


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

---