Evidence for glutamate as the olfactory receptor cell neurotransmitter

1994 ◽  
Vol 71 (6) ◽  
pp. 2557-2561 ◽  
Author(s):  
D. A. Berkowicz ◽  
P. Q. Trombley ◽  
G. M. Shepherd
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Nerve Stimulation ◽  
Olfactory Receptor ◽  
Olfactory Receptor Neuron ◽  
Olfactory Nerve ◽  
Nmda Receptor Antagonist ◽  
Receptor Antagonists ◽  
Cell Recording ◽  
Tufted Cells

1. Synaptic transmission between olfactory receptor neurons and mitral/tufted cells was examined using a whole-cell recording technique in a hemisected preparation of the turtle olfactory bulb. To determine the olfactory receptor neuron transmitter, we isolated components of the synaptic response of mitral/tufted cells to olfactory nerve stimulation using postsynaptic receptor antagonists. 2. Low-intensity stimulation of the olfactory nerve evoked monosynaptic excitatory postsynaptic potentials in mitral/tufted cells that consisted of a rapid and prolonged depolarization with little contribution from other bulb neurons. The exogenous application of glutamate mimicked the response of mitral/tufted cells to olfactory nerve stimulation. 3. Olfactory nerve stimulation evoked in mitral/tufted cells a two component response that was reversibly blocked by glutamate receptor antagonists. The first, a rapid depolarization of short duration, was sensitive to the non-N-methyl-D-aspartate (NMDA) receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX); the second, a depolarization of slower onset but longer duration, was sensitive to the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP5). When DNQX and AP5 were both present the postsynaptic response was completely abolished. These results strongly support the notion that glutamate is the neurotransmitter at the olfactory nerve to mitral/tufted cell synapse.

scholarly journals Identification of novel and structurally diverse N-Methyl-D-Aspartate Receptor Antagonists: Successful Application of Pharmacophore Modeling, Virtual Screening and Molecular Docking

2018 ◽  
Author(s):  
Mukta Sharma ◽  
Anupama Mittal ◽  
Aarti Singh ◽  
Ashwin K. Jainarayanan ◽  
Sarvesh Kumar Paliwal
Keyword(s):  
Hydrogen Bond ◽  
Molecular Docking ◽  
Nmda Receptor ◽  
Virtual Screening ◽  
Alzheimer Disease ◽  
Receptor Antagonist ◽  
In Silico ◽  
Nmda Receptor Antagonist ◽  
Receptor Antagonists ◽  
Hydrogen Bond Acceptor

ABSTRACTIn view of “excitotoxic” effects of glutamate, wherein excessive excitatory input causes increase in intracellular Ca2+ and ultimately cell death, NMDA receptor has emerged as an important target for treatment and prevention of several neurological disorders, like Alzheimer disease. Prompted by the successful application of in-silico pharmacophore-based virtual screening in lead identification, we have made an effort to implement in-silico protocols to identify novel NMDA receptor antagonist. A series of novel benzo[b]quinolizinium cations as NMDA receptor antagonists have been used as a starting point to develop prognostic pharmacophore models. The most predictive pharmacophore model (hypothesis 1), consisting of four features, namely, one hydrogen bond acceptor, one hydrophobic and two ring aromatic, showed a correlation (r) of 0.89, root mean square of 0.259, and the cost difference of 43.01 bits between null and fixed cost. The model was thoroughly validated and subjected to a chemical database search, which lead to the identification of 400 hits from NCI and Maybridge databases which were checked for Lipinski’s violation and predictive potency.This reduced the list to 10 compounds, out of which, two most potent compounds were subjected to molecular docking using Libdock software and interestingly, all the docked conformations showed hydrogen bond interactions with important amino acids Tyr214, His88, Thr174, Val169 and Arg121. In summary, through our validated pharmacophore-based virtual screening protocol, we have identified two potent, structurally diverse, druggable and novel NMDA receptor antagonist which might be of great help to address the unmet medical need of Alzheimer disease.

Ketamine and other NMDA receptor antagonists

2010 ◽  
pp. 115-124
Author(s):  
Marie Fallon ◽  
Cameron Fergus ◽  
Barry J.A. Laird
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Nmda Receptor Antagonist ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Oral Ketamine ◽  
First Pass Metabolism ◽  
First Pass ◽  
Pass Metabolism

Ketamine is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist and is most effective in pain states where hyper-excitability is established Ketamine undergoes first-pass metabolism to norketamine, which is a more potent analgesic than ketamine. This can explain why oral ketamine is more potent than parenteral ketamine...

Imaging NMDA- and kainate-induced intrinsic optical signals from the hippocampal slice

1996 ◽  
Vol 76 (4) ◽  
pp. 2707-2717 ◽  
Author(s):  
R. D. Andrew ◽  
J. R. Adams ◽  
T. M. Polischuk
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Ampa Receptors ◽  
Hippocampal Slice ◽  
Field Potential ◽  
Nmda Receptor Antagonist ◽  
Light Transmittance ◽  
Stratum Radiatum ◽  
Cell Swelling ◽  
Tissue Resistance

1. Brain ischemia causes excess release and accumulation of glutamate that binds to postsynaptic receptors. This opens ionotropic channels that mediate neuronal depolarization and ionic fluxes that can lead to neuronal death. 2. The CA1 pyramidal cell region of the hippocampus is particularly susceptible to this neurotoxic process. Brain cell swelling is considered an early excitotoxic event, but remains poorly under stood and documented. As cells swell, light transmittance (LT) increases through brain tissue, so we hypothesized that brief exposure to glutamate agonists would elicit cell swelling that could be imaged in real time in the hippocampal slice. 3. A 1-min bath application of 100 microM N-methyl-D-aspartate (NMDA) or 100 microM kainate at 22 degrees C greatly increased LT, particularly in the dendritic regions of CA1. The response peaked by 2-3 min and slowly reversed over the subsequent 20 min following exposure. Peak LT increases were > 50% in CA1 stratum radiatum and > 20% in both CA1 stratum oriens and the dendritic region of the dentate gyrus, all areas with a high concentration of NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. The CA3 stratum radiatum, which contains fewer of these receptors, showed a comparatively small LT increase. 4. The NMDA receptor antagonist 2-amino-5-phosphonovalerate (AP-5) [but not 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)] blocked the CA1 response to NMDA, whereas the non-NMDA receptor antagonist CNQX (but not AP-5) blocked the response to kainate. The relative tissue resistance measured across CA1 stratum radiatum increased after NMDA or kainate exposure with a time course similar to the LT change described above. The increase in relative tissue resistance was blocked by kynurenate, a nonspecific glutamate antagonist. Increases in both LT and tissue resistance provide two independent lines of evidence that cell swelling rapidly developed in CA1 dendritic areas after activation of NMDA or AMPA receptors. 5. This swelling at 22 degrees C was accompanied by a temporary loss of the evoked CA1 field potential. However, at 37 degrees C the dendritic swelling rapidly progressed to an irreversible LT increase (swelling) of the CA1 cell bodies accompanied by a permanent loss of the evoked field. 6. We propose that dendritic swelling mediated by NMDA and AMPA receptors is an early excitotoxic event that can herald permanent damage to CA1 neurons, those cells most vulnerable to ischemic insult.

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