Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:6893-26-1 (glutamate)
 73,096 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study investigated the delayed and persistent effects of 4 beta-phorbol 12,13-dibutyrate (PDBu) on the K(+)-evoked release of endogenous glutamate and dynorphin B-like immunoreactivity from a subcellular fraction (P3) that is enriched in hippocampal mossy fiber synaptosomes. It is demonstrated that the alpha, beta, gamma, epsilon, and zeta isoforms of protein kinase C (PKC) are present in the P3 fraction obtained using the guinea pig hippocampus as starting tissue. The K(+)-evoked release of glutamate was found to be selectively enhanced when mossy fiber-enriched synaptosomes were preincubated with PDBu for 15 minutes and extensively washed with a PDBu-free medium. The persistent enhancement of glutamate release observed under this condition was not reversed by the protein kinase inhibitor staurosporine and was desensitized to the potentiating effects of an acute reexposure to PDBu. The overall content and activity of PKC was not substantially altered during the initial 15 minutes of treatment with PDBu (10 microM). More prolonged pretreatments with PDBu altered the substrate specificity of PKC and decreased the content of all PKC isoforms, but did not reverse the facilitation of glutamate release that followed preincubation in the presence of PDBu. It is concluded that the persistent activation of PKC enhances K(+)-evoked glutamate release from hippocampal mossy fiber-enriched synaptosomes and that, once established, this presynaptic facilitation is sustained by a process that is no longer directly dependent on continued PKC phosphotransferase activity.
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PMID:Transduction of a protein kinase C-generated signal into the long-lasting facilitation of glutamate release. 810 80

The binding characteristics of histogranin (HN), an endogenous peptide first recognized for its antagonism of N-methyl-D-aspartate (NMDA) responses, were determined in membrane preparations of rat brain. [125I][Ser1]HN, a stable bioactive analog of HN, bound specifically and reversibly to a homogenous population of high-affinity sites with a Kd of 25 nM and a Bmax of 410 fmol/mg protein. The binding of [125I][Ser1]HN increased linearly with membrane protein concentration and was destroyed upon membrane pretreatment with trypsin. The binding displayed rapid association and dissociation kinetics and was blocked by peptides possessing close homology with HN in the following order: [Ser1]HN-(1-15) > HN > [Ser1]HN-(1-14) > HN-(2-15) > [Ser1]-HN-(1-10) > HN-(6-10). Unrelated peptides such as substance P, beta-endorphin, neuropeptide Y, [Met5]enkephalin, [Leu5]enkephalin, dynorphin A(1-13) and neuromedin C were inactive in competition binding assays against [125I]Ser1]HN. Ligands of the binding domains of the NMDA receptor, such as (+)3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, (+) 5-methyl-10,11-dihydro 5H-dibenzo[a, d]cyclohepten-5,10-imine hydrogen maleate, 1-N-(2-thienyl)cyclohexylpiperidine, glycine and glutamate were also ineffective in competing for [125I][Ser1]HN binding sites. Interestingly, specific ligands for the polyamine site on the NMDA receptor, as well as the cations Mg++ and Zn++ inhibited [125I][Ser1]HN binding. The polyamine antagonist diethylenetriamine produced a noncompetitive inhibition with an IC50 (175 nM) comparable to that of HN (75 nM). The cations Zn++ and Mg++ displaced [125I][Ser1]HN binding with IC50 values of 18 and 240 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of [125I][Ser1]histogranin binding sites in rat brain. 822 61

In the present study we have shown by single afferent unit recording in electroreceptors of skates (the ampullae of Lorenzini) that the synthetic analogue of leu-enkephalin, dalargin (DAL) at concentrations between 10(-6)-10(-10) M cause a concentration-dependent decrease in the resting discharge frequency as well as a decrease in stimulus evoked responses. The specific opiate antagonist naloxone (NAL, 10(-6) M) antagonizes responses induced by DAL. DAL depresses the excitatory action of L-glutamate (L-GLU). The data obtained speak in favour of the presence of opiate receptors at the synaptic membrane of the ampullae of Lorenzini.
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PMID:Actions of dalargin upon single unit activity in the ampullae of Lorenzini of the skate Raja clavata. 838 18

Synapses of the hippocampal mossy fiber pathway exhibit several characteristic features, including a unique form of long-term potentiation that does not require activation of the N-methyl-D-aspartate receptor by glutamate, a complex postsynaptic architecture, and sprouting in response to seizures. However, these connections have proven difficult to study in hippocampal slices because of their relative paucity (<0.4%) compared to commissural-collateral synapses. To overcome this problem, we have developed a novel dissociated cell culture system in which we have enriched mossy fiber synapses by increasing the ratio of granule-to-pyramidal cells. As in vivo, mossy fiber connections are composed of large dynorphin A-positive varicosities contacting complex spines (but without a restricted localization). The elementary synaptic connections are glutamatergic, inhibited by dynorphin A, and exhibit N-methyl-D-aspartate-independent long-term potentiation. Thus, the simplicity and experimental accessibility of this enriched in vitro mossy fiber pathway provides a new perspective for studying nonassociative plasticity in the mammalian central nervous system.
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PMID:Reconstitution of the hippocampal mossy fiber and associational-commissural pathways in a novel dissociated cell culture system. 864 67

The development of chronically painful states following peripheral nerve injury may involve different mechanisms depending on the nature and extent of the nerve lesion. The altered spinal neurochemistry of two substances, the excitatory amino acid glutamate operating via the N-methyl-D-aspartate receptor and the endogenous opioid peptide dynorphin, have been implicated in behavioral sequelae that follow partial peripheral nerve injury. In addition, dynorphin has nonopioid functions which may involve the N-methyl-D-aspartate receptor. We investigated two hypotheses: that the development of mechanical allodynia following complete nerve injury is not greatly influenced by the N-methyl-D-aspartate receptor, and that spinal dynorphin and glutamate expression is interdependent. These studies employed sciatic cryoneurolysis, a complete but transient peripheral nerve injury that results in a delayed mechanical allodynia beginning 21-28 days after injury. Rats were administered dizocipline maleate (MK-801) at 0.25 mg/kg twice per day intraperitoneally from days 0-7 or from days 0-21 post-lesion to pre-emptively block the N-methyl-D-aspartate receptor. In a separate group of rats, an antibody to dynorphin was administered intraperitoneally at 16.6 mg/kg twice per day from days 14 to 21 post-lesion. For all groups, the outcome of allodynia behavior was assessed using von Frey filaments at 42 days post-lesion and the resulting dynorphin and glutamate immunoreactivity in the substantia gelatinosa was measured using proportional area stained and relative optical density, respectively. Only the 0-7 day MK-801 treatment increased the resulting mechanical thresholds significantly (mean +/- S.E.M. 7.0 +/- 1.2 g) when compared to saline-injected animals (3.9 +/- 0.6 g). However, this effect did not prevent allodynia since baseline thresholds were 12 or 15 g for each group. With regard to resulting spinal immunoreactivity, anti-dynorphin antibody treatment significantly increased glutamate immunoreactivity when compared to saline-treated animals (mean relative optical density +/- S.E.M. = 807.2 +/- 3.6 versus 779.6 +/- 8.3, respectively; P = 0.01) at 42 days post-lesion. We conclude that the development of allodynia following sciatic cryoneurolysis peripheral nerve injury involved a minimal contribution from N-methyl-D-aspartate receptor activity. In addition, this study demonstrated that decreasing available dynorphin using antiserum had a significant and lasting effect on spinal glutamate expression without altering the outcome of allodynia. These conclusions suggest that etiological mechanisms leading to pain behaviors are not equal for all nerve injuries, and that altering kappa opioid levels can affect glutaminergic pathways at a substantially later time.
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PMID:Pre-emptive dynorphin and N-methyl-D-aspartate glutamate receptor antagonism alters spinal immunocytochemistry but not allodynia following complete peripheral nerve injury. 873 21

The last two decades have witnessed major progress in the understanding of cochlear mechanical functioning, and in the emergence of cochlear neurochemistry and neuropharmacology. Recent models describe active processes within the cochlea that amplify and sharpen the mechanical response to sound. Although it is widely accepted that outer hair cells (OHCs) contribute to these processes, the nature of the medial efferent influence on cochlear mechanics needs further clarification. Acetylcholine (ACh) is the major transmitter released onto OHCs during the stimulation of these efferents. The inhibitory influence of this system is mediated by post- and presynaptic nicontinic and muscarinic receptors and the role of other neuroactive substances [gamma-aminobutyric acid (GABA), calcitonin gene-related peptide (CGRP), adenosine 5'-triphosphate (ATP) or nitric oxide (NO)] remains to be determined. The inner hair cells (IHCs) that transduce the mechanical displacements into neural activity, release glutamate on receptor-activated channels of AMPA, kainate, and NMDA types. This synapse is in turn controlled and/or regulated by the lateral efferents containing a cocktail of neuroactive substances (ACh, GABA, dopamine, enkephalins, dynorphin, CGRP). This glutamatergic nature of the IHCs is responsible for the acute destruction of the nerve endings and subsequently for neuronal death, damage usually described in various cochlear diseases (noise-induced hearing losses, neural presbycusis and certain forms of sudden deafness or peripheral tinnitus). These pathologies also include a regrowth of new dendritic processes by surviving neurons up to IHCs. Understanding the subtle molecular mechanisms which underly the control of neuronal excitability, synaptic plasticity and neuronal death in cochlear function and disease is a very important issue for the development of future therapies.
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PMID:Chemical synaptic transmission in the cochlea. 878 31

A neutral endopeptidase (NEP) from Lactococcus lactis has recently been cloned and shown to contain high sequence homology with the human neutral endopeptidase, endopeptidase 24.11 (I. Mierau et al., J. Bacteriol. 175, 2087-2096, 1993). The gene for the neutral endopeptidase from L. lactis was cloned into the pQE expression vector, resulting in the fusion of a hexahistidine at the N-terminus. The recombinant enzyme was expressed to high levels in Escherichia coli (approximately 10 mg/liter of culture) and purified to homogeneity in a two-step procedure. A number of peptides were studied as substrates for the enzyme. The enzyme cleaves the following peptides at the Gly3-Phe4 bond: enkephalins, dynorphins A-6, A-8, A-9, A-10, A-13, and A-17, and alpha-neo-endorphin. In addition the enzyme hydrolyzes bradykinin, substance P, beta-endorphin, ACTH, and VIP. Although the cleavage patterns observed are similar to that seen with mammalian neutral endopeptidase, the lactococcal enzyme more efficiently cleaves larger peptide substrates. As observed with the mammalian neutral endopeptidase, the lactococcal enzyme exhibits higher kcat/K(m) values for the enkephalins than for their corresponding amides, indicating the functionality of an active-site arginine. Inactivation of the lactococcal endopeptidase by diethyl pyrocarbonate and protection afforded by the substrate dynorphin A-6 indicate the functionality of a positionally conserved active-site histidine. This was confirmed by demonstrating that conversion of this histidine, histidine 587, to glutamine generated inactive enzyme. Similarly, conversion of the putative zinc ligand glutamate 535 to glutamine led to inactive enzyme. These studies indicate a conservation of critical catalytic residues between the two enzymes and suggest that the lactococcal endopeptidase is a better model than thermolysin for the mammalian enzyme.
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PMID:Heterologous expression and characterization of recombinant Lactococcus lactis neutral endopeptidase (neprilysin). 880 62

The effect of cholecystokinin peptides on the release of dynorphin B, aspartate, glutamate, dopamine and GABA in the neostriatum and substantia nigra of the rat was investigated using in vivo microdialysis. Sulphated cholecystokinin-8S in the dialysis perfusate (1-100 microM) induced a concentration-dependent increase in extracellular dynorphin B and aspartate levels, both in the neostriatum and substantia nigra. Striatal dopamine levels were only increased by 100 microM of cholecystokinin-8S, while in the substantia nigra they were increased by 10-100 microM of cholecystokinin-8S. Extracellular GABA and glutamate levels were increased following 100 microM of cholecystokinin-8S only. Striatal cholecystokinin-8S administration also produced a significant increase in nigral dynorphin B levels. Local cholecystokinin-4 (100 microM) produced a moderate, but significant, increase of extracellular dynorphin B and aspartate levels in the neostriatum and substantia nigra. No effect was observed on the other neurotransmitters investigated. A 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway did not affect the increases in dynorphin B and aspartate levels produced by local administration of cholecystokinin-8S. Basal extracellular GABA levels were increased significantly in both the neostriatum and substantia nigra ipsilateral to the lesion. Nigral glutamate and aspartate levels were also increased in the lesioned substantia nigra, but in the lesioned neostriatum aspartate levels were decreased. The cholecystokinin-B antagonist L-365,260 (20 mg/kg, s.c.), but not the cholecystokinin-A antagonist L-364,718 (devazepide; 20 mg/kg, s.c.), significantly inhibited the effect of cholecystokinin-8S on striatal dynorphin B and aspartate levels. In the substantia nigra, however, the effect of cholecystokinin-8S on dynorphin B and aspartate levels was inhibited to a similar extent by both L-365,260 and L-364,718. Pretreatment with L-364,718, but not with L-365.260, prevented the increase in nigral dopamine levels produced by nigral cholecystokinin-8S administration. Taken together, these results suggest that cholecystokinin-8S modulates dynorphin B and aspartate release in the neostriatum and substantia nigra of the rat via different receptor mechanisms. In the neostriatum, the effect of cholecystokinin-8S on dynorphin B and aspartate release is mediated via the cholecystokinin-B receptor subtype, while in the substantia nigra, cholecystokinin-8S modulates dynorphin B and aspartate release via both cholecystokinin-A and cholecystokinin-B receptor subtypes. Cholecystokinin-8S modulates dopamine release mainly in the substantia nigra, via the cholecystokinin-A receptor subtype.
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PMID:Modulation of neurotransmitter release by cholecystokinin in the neostriatum and substantia nigra of the rat: regional and receptor specificity. 888 75

In vivo microdialysis was used to study the effects of systemic, as well as intracerebral administration of morphine and naloxone on dynorphin B release in neostriatum and substantia nigra of rats. The release of dopamine (DA), gamma-aminobutyric acid (GABA), glutamate (Glu) and aspartate (Asp) was also investigated. Systemic injection of morphine (1 mg/kg s.c.) induced long-lasting increases in extracellular dynorphin B and GABA levels in the substantia nigra, whereas DA, Glu and Asp levels, measured in the same region, were not significantly affected. No effect on striatal neurotransmitter levels was observed following systemic morphine administration. Local perfusion of the substantia nigra with morphine (100 microM) through the microdialysis probe also increased nigral dynorphin B and GABA levels. Perfusion of the neostriatum with morphine (100 microM) significantly increased GABA and dynorphin B levels in the ipsilateral substantia nigra, but no effect was observed locally. Naloxone blocked the effect of systemic morphine administration on nigral dynorphin B and GABA release, already at a dose of 0.2 mg/kg s.c. Naloxone alone, given either systemically (0.2-4 mg/kg s.c.) or intracerebrally (1-100 microM), did not affect dynorphin B or amino acid levels, either in neostriatum or in substantia nigra. However, naloxone produced a concentration-dependent increase in DA levels. The present results indicate that systemic morphine administration stimulates the release of dynorphin B in the substantia nigra, probably by activating the mu-subtype of opioid receptor, since the effect of morphine on nigral dynorphin B and GABA was antagonized by a low dose of naloxone. The increase in extracellular DA levels produced by high concentrations of naloxone, both in neostriatum and substantia nigra, indicates a disinhibitory effect of this drug on DA release, probably via a non-mu subtype of opioid receptors located on nigro-striatal DA neurones.
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PMID:Effect of morphine on dynorphin B and GABA release in the basal ganglia of rats. 896 65

In vivo microdialysis was used to study the effect of secretogranin II-derived peptides on dynorphin B (Dyn B), dopamine, gamma-aminobutyric acid (GABA), glutamate and aspartate release in the substantia nigra and neostriatum of halothane-anaesthesized rats. In the substantia nigra, local infusion of secretoneurin (secretogranin II 154-186) (1-50 microM) increased, in a concentration-dependent manner, extracellular aspartate, glutamate, Dyn B, dopamine and GABA levels. The effect was particularly prominent on aspartate and glutamate levels which, following 50 microM of secretoneurin, were increased by > 20 and > 10 fold, respectively. However, the effect of secretoneurin on Dyn B release appeared to be more specific, since a significant increase (> 20 fold) was already observed following 1 microM of secretoneurin. In the neostriatum, Dyn B, glutamate, aspartate and GABA levels were also increased by local secretoneurin infusion, but the effect was less prominent than in the substantia nigra. In the substantia nigra, only Dyn B levels were significantly increased following infusion of 10 microM of the secretoneurin-C terminal (secretoneurin-15C), whereas Dyn B and GABA levels were increased by the same concentration of the secretogranin II C terminus (YM). Only glutamate and aspartate levels were increased by local infusion of 10 microM of secretogranin II 133-151 (LF), a peptide adjacent to secretoneurin in the primary amino acid sequence. In the neostriatum, Dyn B and GABA levels were increased by 10 microM of secretoneurin-15C. Dyn B levels were also increased by 10 microM of YM, and glutamate and aspartate levels were increased by 10 microM of both YM and LF. Thus secretogranin II-derived peptides affect extracellular levels of several putative neurotransmitter systems monitored in the basal ganglia of the rat with in vivo microdialysis. The effect of Dyn B appears to be specific and related to a physiological role of secretoneurin, since (i) it occurs in an area where secretoneurin-immunocytochemistry has been observed, (ii) is exerted at comparatively low concentrations, and (iii) is mimicked by secretoneurin-15C. The increases in excitatory amino acid levels produced by high concentrations of secretoneurin and other secretogranin II-derived peptides reflect, perhaps, a potential neurotoxicity produced by abnormal accumulation of these peptides.
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PMID:Effects of secretogranin II-derived peptides on the release of neurotransmitters monitored in the basal ganglia of the rat with in vivo microdialysis. 897 31


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