scholarly journals Distribution of Extrasynaptic NMDA Receptors on Neurons

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Ronald S. Petralia
Keyword(s):  
Nervous System ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Cell Damage ◽  
Receptor Activation ◽  
Negative Influence ◽  
Scaffolding Proteins ◽  
Functional Consequences ◽  
Receptor Clusters ◽  
Nmda Receptor Activation

NMDA receptors are found in both synaptic and extrasynaptic locations on neurons. NMDA receptors also can be found on neurons in early stages prior to synaptogenesis, where they may be involved in migration and differentiation. Extrasynaptic NMDA receptors typically are associated with contacts with adjacent processes such as axons and glia. Extrasynaptic NMDA receptor clusters vary in size and may form associations with scaffolding proteins such as PSD-95 and SAP102. The best-characterized extrasynaptic NMDA receptors contain NR1 and NR2B subunits. Extrasynaptic NMDA receptors may be activated by glutamate spillover from synapses or from ectopic release of glutamate. Consequently, extrasynaptic NMDA receptor activation may occur under different circumstances than that for synaptic NMDA receptors, indicating different functional consequences for the neuron. In some cases, activation of extrasynaptic NMDA receptors may have a negative influence on the neuron, leading to cell damage and death, as may occur in some major diseases of the nervous system.

The effect of varying stimulus intensity on NMDA-receptor activity in cat visual cortex

1990 ◽  
Vol 64 (5) ◽  
pp. 1413-1428 ◽  
Author(s):  
K. Fox ◽  
H. Sato ◽  
N. Daw
Keyword(s):  
Visual Cortex ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Receptor Activation ◽  
Visual Response ◽  
Background Luminance ◽  
Stimulus Contrast ◽  
Cat Visual Cortex ◽  
Low Levels ◽  
Nmda Receptor Activation

1. A study was made of the relative contribution of N-methyl-D-aspartate (NMDA) and non-NMDA receptors to the visual responses of cells in different layers of the cat visual cortex at different levels of excitatory drive (which was varied by altering the stimulus contrast). 2. Receptive fields were mapped for 121 cells in area 17 of cat cortex. Cells were characterized to determine the optimal visual stimulus, the brightness of which was then varied relative to background luminance to construct a contrast-response (C-R) curve for each cell. Curves were made during control conditions and during application of agonists (NMDA and quisqualate) and/or antagonists [(D)-2-amino-5-phosphonovaleric acid (D-APV) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)] to examine the excitatory amino acid components of the visual response. 3. Threshold responses were obtained with stimuli between 1/60 and 1.8 X background luminance. The cell response, measured by firing rate, was linearly related to stimulus contrast over 1-2 decades and saturated at higher contrasts. 4. Application of APV reduced the slope of the linear portion of the C-R curve for cells located in layers II and III (average reduction, 59% of control). APV did not decrease the threshold to stimulation. The "just suprathreshold" responses to stimulation were reduced by the same proportion as the saturation responses for individual cells. The principal effect was therefore to reduce the gain of the C-R curve in these layers. 5. Application of APV reduced the spontaneous activity of cells located in layers IV, V, and VI with little if any effect on the gain of the C-R curve. This suggests a tonic background level of NMDA-receptor activation in these layers, which is not directly related to the visual response. 6. Low levels of NMDA increased the gain of the C-R curve in layers II/III and V/VI. On the other hand, low levels of quisqualate increased the overall level of firing without affecting the gain of the C-R curve. NMDA did not increase the gain of the curve in layer IV. 7. These experiments show that visual stimuli that produce just suprathreshold responses activate NMDA receptors. The degree of activation is proportionally the same for small responses and large responses for an individual cell. Rather than finding a threshold for NMDA-receptor activation, a continuous range of NMDA-receptor influence was observed over the entire response range.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals NMDA Receptor Activation by Spontaneous Glutamatergic Neurotransmission

2009 ◽  
Vol 101 (5) ◽  
pp. 2290-2296 ◽  
Author(s):  
Felipe Espinosa ◽  
Ege T. Kavalali
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Ampa Receptor ◽  
Cortical Neurons ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Receptor Activity ◽  
Resting Membrane Potential ◽  
Nmda Current ◽  
Nmda Receptor Activation

Under physiological conditions N-methyl-d-aspartate (NMDA) receptor activation requires coincidence of presynaptic glutamate release and postsynaptic depolarization due to the voltage-dependent block of these receptors by extracellular Mg2+. Therefore spontaneous neurotransmission in the absence of action potential firing is not expected to lead to significant NMDA receptor activation. Here we tested this assumption in layer IV neurons in neocortex at their resting membrane potential (approximately −67 mV). In long-duration stable recordings, we averaged a large number of miniature excitatory postsynaptic currents (mEPSCs, >100) before or after application of dl-2 amino 5-phosphonovaleric acid, a specific blocker of NMDA receptors. The difference between the two mEPSC waveforms showed that the NMDA current component comprises ∼20% of the charge transfer during an average mEPSC detected at rest. Importantly, the contribution of the NMDA component was markedly enhanced at membrane potentials expected for the depolarized up states (approximately −50 mV) that cortical neurons show during slow oscillations in vivo. In addition, partial block of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor component of the mEPSCs did not cause a significant reduction in the NMDA component, indicating that potential AMPA receptor-driven local depolarizations did not drive NMDA receptor activity at rest. Collectively these results indicate that NMDA receptors significantly contribute to signaling at rest in the absence of dendritic depolarizations or concomitant AMPA receptor activity.

Activation of NMDA receptors linked to modulation of voltage-gated ion channels and functional implications

2003 ◽  
Vol 284 (3) ◽  
pp. C757-C768 ◽  
Author(s):  
S. F. Davis ◽  
C. L. Linn
Keyword(s):  
Steady State ◽  
Membrane Potential ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Receptor Activation ◽  
Calcium Currents ◽  
Horizontal Cells ◽  
Voltage Gated ◽  
Functional Implications ◽  
Nmda Receptor Activation

Catfish ( Ictalurus punctatus) cone horizontal cells contain N-methyl-d-aspartate (NMDA) receptors, the function of which has yet to be determined. In the present study, we have examined the effect of NMDA receptor activation on voltage-gated ion channel activity. NMDA receptor activation produced a long-term downregulation of voltage-gated sodium and calcium currents but had no effect on the delayed rectifying potassium current. NMDA's effect was eliminated in the presence of AP-7. To determine whether NMDA receptor activation had functional implications, isolated catfish cone horizontal cells were current clamped to mimic the cell's physiological response. When horizontal cells were depolarized, they elicited a single depolarizing overshoot and maintained a depolarized steady state membrane potential. NMDA reduced the amplitude of the depolarizing overshoot and increased the depolarized steady-state membrane potential. Both effects of NMDA were eliminated in the presence of AP-7. These results support the hypothesis that activation of NMDA receptors in catfish horizontal cells may affect the type of visual information conveyed through the distal retina.

scholarly journals Probing the activation sequence of NMDA receptors with lurcher mutations

2012 ◽  
Vol 140 (3) ◽  
pp. 267-277 ◽  
Author(s):  
Swetha E. Murthy ◽  
Tamer Shogan ◽  
Jessica C. Page ◽  
Eileen M. Kasperek ◽  
Gabriela K. Popescu
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Single Channel ◽  
Receptor Activation ◽  
Dissociation Rate ◽  
Activation Mechanism ◽  
Structural Determinants ◽  
Ionic Flux ◽  
Single Channel Currents ◽  
Nmda Receptor Activation

N-methyl-d-aspartate (NMDA) receptor activation involves a dynamic series of structural rearrangements initiated by glutamate binding to glycine-loaded receptors and culminates with the clearing of the permeation pathway, which allows ionic flux. Along this sequence, three rate-limiting transitions can be quantified with kinetic analyses of single-channel currents, even though the structural determinants of these critical steps are unknown. In inactive receptors, the major permeation barrier resides at the intersection of four M3 transmembrane helices, two from each GluN1 and GluN2 subunits, at the level of the invariant SYTANLAAF sequence, known as the lurcher motif. Because the A7 but not A8 residues in this region display agonist-dependent accessibility to extracellular solutes, they were hypothesized to form the glutamate-sensitive gate. We tested this premise by examining the reaction mechanisms of receptors with substitutions in the lurcher motifs of GluN1 or GluN2A subunits. We found that, consistent with their locations relative to the proposed activation gate, A8Y decreased open-state stability, whereas A7Y dramatically stabilized open states, primarily by preventing gate closure; the equilibrium distribution of A7Y receptors was strongly shifted toward active states and resulted in slower microscopic association and dissociation rate constants for glutamate. In addition, for both A8- and A7-substituted receptors, we noticed patterns of kinetic changes that were specific to GluN1 or GluN2 locations. This may be a first indication that the sequence of discernible kinetic transitions during NMDA receptor activation may reflect subunit-dependent movements of M3 helices. Testing this hypothesis may afford insight into the activation mechanism of NMDA receptors.

Thiopental Inhibits Increases in [Ca2+]iInduced by Membrane Depolarization, NMDA Receptor Activation, and Ischemia in Rat Hippocampal and Cortical Slices 

1998 ◽  
Vol 89 (2) ◽  
pp. 456-466 ◽  
Author(s):  
Ren-Zhi Zhan ◽  
Naoshi Fujiwara ◽  
Hiroshi Endoh ◽  
Tomohiro Yamakura ◽  
Kiichiro Taga ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Hippocampal Slices ◽  
Receptor Activation ◽  
Membrane Depolarization ◽  
In Vitro Ischemia ◽  
High K ◽  
Nmda Receptor Activation ◽  
Cortical Slices

Background This study examined the effects of thiopental on intracellular calcium ([Ca2+]i) changes induced by membrane depolarization, N-methyl-D-aspartate (NMDA) receptor activation, and ischemia. Methods Experiments were performed in brain slices prepared from Wistar rats. [Ca2+]i measurements were taken on the CA1 pyramidal cell layer of the hippocampus or layers II to III of the somatosensory cortex using the fura-2 fluorescence technique. Membrane depolarization and NMDA receptor activation were induced by exposing slices to 60 mM K+ and 100 microM NMDA, respectively. In vitro ischemia was induced by superfusing slices with glucose-free Krebs solution equilibrated with 95% nitrogen and 5% carbon dioxide. Thiopental was applied 5 min before application of high K+ and NMDA, or before in vitro ischemia. Results Ischemia for 15 min produced a characteristic [Ca2+]i increase in both hippocampal and cortical slices. Thiopental prolonged the latency to the appearance of the [Ca2+]i plateau and reduced the magnitudes of increase in [Ca2+]i 8, 10, and 15 min after the onset of ischemia. Thiopental also suppressed the high K+- and NMDA-induced [Ca2+]i increases. The NMDA-induced [Ca2+]i increases were attenuated to a greater extent in cortical slices than were those in hippocampal slices. The inhibition of thiopental on the 200-microM NMDA-mediated [Ca2+]i response was confirmed in cultured cortical neurons. Conclusions The results indicate that thiopental attenuates ischemia-induced [Ca2+]i increases in the hippocampus and cortex in vitro, probably because of its inhibition of both voltage-gated calcium channels and NMDA receptors. The regionally different inhibition of thiopental on NMDA receptors may relate to its region-specific action against ischemia.

scholarly journals Contributions by N-terminal Domains to NMDA Receptor Currents

2020 ◽  
Author(s):  
Stacy A. Amico-Ruvio ◽  
Meaghan A. Paganelli ◽  
Jamie A. Abbott ◽  
Jason M. Myers ◽  
Eileen M Kasperek ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Receptor Activation ◽  
Core Domain ◽  
Gating Mechanism ◽  
Mode Transitions ◽  
Channel Currents ◽  
Nmda Receptor Activation ◽  
Terminal Domains

ABSTRACTTo investigate the role of the N-terminal domains (NTDs) in NMDA receptor signaling we used kinetic analyses of one-channel currents and compared the reaction mechanism of recombinant wild-type GluN1/GluN2A and GluN1/GluN2B receptors with those observed for NDT-lacking receptors. We found that truncated receptors maintained the fundamental gating mechanism characteristic of NMDA receptors, which includes a multi-state activation sequence, desensitization steps, and mode transitions. This result establishes that none of the functionally-defined NMDA receptor activation events require the NTD. Notably, receptors that lacked the entire NTD layer retained isoform-specific kinetics. Together with previous reports, these results demonstrate that the entire gating machinery of NMDA receptors resides within a core domain that contains the ligand-binding and the channel-forming transmembrane domains, whereas the NTD and C-terminal layers serve modulatory functions, exclusively.

scholarly journals Structure, Function, and Pharmacology of NMDA Receptor Channels

2014 ◽  
pp. S191-S203 ◽  
Author(s):  
V. VYKLICKY ◽  
M. KORINEK ◽  
T. SMEJKALOVA ◽  
A. BALIK ◽  
B. KRAUSOVA ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Synaptic Transmission ◽  
Nmda Receptors ◽  
Neural Plasticity ◽  
Receptor Activation ◽  
Neuroprotective Drugs ◽  
Receptor Inhibition ◽  
Nmda Receptor Function ◽  
The One ◽  
Nmda Receptor Activation

NMDA receptors have received much attention over the last few decades, due to their role in many types of neural plasticity on the one hand, and their involvement in excitotoxicity on the other hand. There is great interest in developing clinically relevant NMDA receptor antagonists that would block excitotoxic NMDA receptor activation, without interfering with NMDA receptor function needed for normal synaptic transmission and plasticity. This review summarizes current understanding of the structure of NMDA receptors and the mechanisms of NMDA receptor activation and modulation, with special attention given to data describing the properties of various types of NMDA receptor inhibition. Our recent analyses point to certain neurosteroids as NMDA receptor inhibitors with desirable properties. Specifically, these compounds show use-dependent but voltage-independent block, that is predicted to preferentially target excessive tonic NMDA receptor activation. Importantly, neurosteroids are also characterized by use-independent unblock, compatible with minimal disruption of normal synaptic transmission. Thus, neurosteroids are a promising class of NMDA receptor modulators that may lead to the development of neuroprotective drugs with optimal therapeutic profiles.

Endogenous NMDA-Receptor Activation Regulates Glutamate Release in Cultured Spinal Neurons

1998 ◽  
Vol 80 (1) ◽  
pp. 196-208 ◽  
Author(s):  
Antoine Robert ◽  
Joel A. Black ◽  
Stephen G. Waxman
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Single Channel ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Receptor Activity ◽  
Spinal Neurons ◽  
Quantal Size ◽  
Endogenous Activity ◽  
Nmda Receptor Activation

Robert, Antoine, Joel A. Black, and Stephen G. Waxman. Endogenous NMDA-receptor activation regulates glutamate release in cultured spinal neurons. J. Neurophysiol. 80: 196–208, 1998. N-methyl-d-aspartate (NMDA) receptor activation plays a fundamental role in the genesis of electrical activity of immature neurons and may participate in activity-dependent aspects of CNS development. A recent study has suggested that NMDA-receptor–mediated glutamatergic neurotransmission might occur in the developing spinal cord via activation of nonsynaptic receptors, but the details of NMDA-receptor activation in the developing CNS are not yet well understood. We describe here a model of cultured spinal neurons that display ongoing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity characterized by spontaneous excitatory postsynaptic currents (EPSCs), with NMDA-receptor activity detectable only as single channel events. dl-2-amino-5-phosphonovaleric acid (100 μM) and tetrodotoxin (TTX) 100 nM each reduced the occurrence of spontaneous AMPA EPSCs; quantal analysis showed a decrease in the number of released quanta but no changes in quantal size, indicating that NMDA-receptor activation and Na+ channel activity affect the generation of spontaneous AMPA EPSCs, at least in part, via mechanisms that impinge on the presynaptic terminal. Once the Mg2+-block was released, activity of NMDA receptors dramatically increased the release of quantal and multiquantal amounts of glutamate, indicating that the NMDA receptors are physiologically coupled to glutamate release. In Mg2+-free solution, TTX application elicited an increase in the number of quantal AMPA EPSCs and a reduction in the number of multiquantal EPSCs, consistent with an effect of NMDA-receptor activation on presynaptic terminals. Our results suggest that endogenous activity at a small number of NMDA receptors can regulate the release of neurotransmitters at developing AMPA synapses.

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