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.

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.

Retinogeniculate EPSPs recorded intracellularly in the ferret lateral geniculate nucleus in vitro: Role of NMDA receptors

1992 ◽  
Vol 8 (6) ◽  
pp. 545-555 ◽  
Author(s):  
Manuel Esguerra ◽  
Young H. Kwon ◽  
Mriganka Sur
Keyword(s):  
Membrane Potential ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Lateral Geniculate Nucleus ◽  
Excitatory Amino Acid ◽  
Optic Tract ◽  
Receptor Activation ◽  
Lateral Geniculate

AbstractWe used an in vitro preparation of the ferret lateral geniculate nucleus (LGN) to examine the role of the NMDA class of excitatory amino acid (EAA) receptors in retinogeniculate transmission. Intracellular recordings revealed that blockade of NMDA receptors both shortened the time course and reduced the amplitude of fast and slow components of excitatory postsynaptic potentials (EPSPs) evoked by optic tract stimulation. The amplitude and width of the EPSPs mediated by NMDA receptors increased as membrane potential was depolarized towards spike threshold. Individual LGN cells were influenced to varying extents by blockade of NMDA receptors; NMDA and non-NMDA receptor blockade together attenuated severely the entire retinogeniculate EPSP. The dependence of all components of retinogeniculate EPSPs (and action potentials) on NMDA receptor activation supports the hypothesis that the NMDA receptor participates in fast (<10 ms) synaptic events underlying conventional retinogeniculate transmission. The voltage dependence of the NMDA receptor-gated conductance suggests strongly that the transmission of retinal information through the LGN is subject to modulation by extraretinal inputs that affect the membrane potential of LGN neurons.

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.

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.

Intrinsic NMDA-Induced Oscillations in Motoneurons of an Adult Vertebrate Spinal Cord Are Masked by Inhibition

1997 ◽  
Vol 77 (2) ◽  
pp. 717-730 ◽  
Author(s):  
Mengia-Seraina Rioult-Pedotti
Keyword(s):  
Spinal Cord ◽  
Membrane Potential ◽  
Nmda Receptor ◽  
Low Frequency ◽  
Receptor Activation ◽  
Intracellular Recordings ◽  
Potential Oscillations ◽  
Frog Spinal Cord ◽  
Nmda Receptor Activation ◽  
Membrane Potential Oscillations

Rioult-Pedotti, Mengia-Seraina. Intrinsic NMDA induced oscillations in motoneurons of an adult vertebrate spinal cord are masked by inhibition. J. Neurophysiol. 77: 717–730, 1997. Low-frequency membrane potential oscillations were induced in motoneurons (MNs) of isolated hemisected frog spinal cords during N-methyl-d-aspartate (NMDA) application. Oscillations required the presence of physiological Mg2+ and preincubation with strychnine, whereas incubation with bicuculline or phaclofen was not effective. Oscillations were evident in intracellular recordings from single MNs and simultaneous extracellular recordings from lumbar ventral roots. In Mg2+-free solution, MNs exhibited irregular transient membrane potential depolarizations that were blocked by d,l-2-amino-5-phosphonopentanoic acid (APV) but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Generation and maintenance of membrane potential oscillations required specific NMDA receptor activation. Oscillations were antagonized by APV but not by CNQX. Strychnine preincubation was required for NMDA to induce oscillations, but was not critical in maintaining them, because oscillations persisted after removal of strychnine. Therefore oscillations are suggested to be an inherent property of the spinal neuronal circuitry. Tetrodotoxin (TTX) blocked spike activity and had a bimodal effect on membrane potential oscillations. Oscillations initially were blocked by TTX, but reappeared spontaneously after 10–40 min. This suggests that maintenance of oscillations, once evoked, does not involve MN firing. Na+ entry through TTX-insensitive Na+ channels and/or NMDA receptor channels, transmembrane Ca2+ flux, Ca2+ release from intracellular stores, and Ca2+ activated K+ channels were critical in controlling the amplitude and frequency of membrane potential oscillations. It is hypothesized that these unmasked intrinsic oscillations in adult frog spinal cord MNs may represent a premetamorphic spinal oscillator involved in tadpole swimming that becomes suppressed during metamorphosis as strychnine-sensitive inhibition becomes more pronounced.

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.

Mechanism linking NMDA receptor activation to modulation of voltage-gated sodium current in distal retina

2003 ◽  
Vol 284 (5) ◽  
pp. C1193-C1204 ◽  
Author(s):  
Scott F. Davis ◽  
Cindy L. Linn
Keyword(s):  
Sodium Channel ◽  
Nmda Receptors ◽  
Sodium Channels ◽  
Calcium Influx ◽  
Receptor Activation ◽  
Horizontal Cells ◽  
Channel Modulation ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Nmda Channels

In this study, we investigated the mechanism that links activation of N-methyl-D-aspartate (NMDA) receptors to inhibition of voltage-gated sodium channels in isolated catfish cone horizontal cells. NMDA channels were activated in voltage-clamped cells incubated in low-calcium saline or dialyzed with the calcium chelator BAPTA to determine that calcium influx through NMDA channels is required for sodium channel modulation. To determine whether calcium influx through NMDA channels triggers calcium-induced calcium release (CICR), cells were loaded with the calcium-sensitive dye calcium green 2 and changes in relative fluorescence were measured in response to NMDA. Responses were compared with measurements obtained when caffeine depleted stores. Voltage-clamp studies demonstrated that CICR modulated sodium channels in a manner similar to that of NMDA. Blocking NMDA receptors with AP-7, blocking CICR with ruthenium red, depleting stores with caffeine, or dialyzing cells with calmodulin antagonists W-5 or peptide 290–309 all prevented sodium channel modulation. These results support the hypothesis that NMDA modulation of voltage-gated sodium channels in horizontal cells requires CICR and activation of a calmodulin-dependent signaling pathway.

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.

Sign in / Sign up

Export Citation Format

Share Document