Molecular Properties and Cell Biology of the NMDA Receptor

Neuropharmacology, 2001

Potentiation of ionotropic glutamate receptor activity by metabotropic glutamate receptors (mGluRs) is thought to modulate activity at glutamatergic synapses in the hippocampus. However, the precise pathway by which this modulation occurs is not well understood. The present study tests the hypothesis that mGluR1-mediated potentiation of N-methyl-D-aspartate receptors (NMDARs) occurs via a phospholipase C (PLC)-initiated cascade. NMDAR functional activity was examined by whole-cell recording from Xenopus oocytes expressing recombinant NMDARs and mGluR1alpha. The mGluR1 agonist (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid (ACPD) significantly potentiated NMDA-elicited currents. mGluR1alpha-mediated potentiation of NMDA responses was eliminated by the PLC inhibitor U-73122. Buffering of intracellular Ca2+ by BAPTA-AM or depletion of intracellular Ca2+ by the Ca2+/ATPase inhibitor thapsigargin greatly reduced ACPD potentiation. ACPD potentiation was reduced by the specific protein kinase C (PKC) inhibitor Ro-32-0432 and eliminated by the broad spectrum kinase inhibitor staurosporine. ACPD produced no further potentiation after potentiation of NMDARs by the PKC-activating phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA). Thus, Group I mGluRs potentiate NMDA responses via activation of PLC; at least part of the potentiation is due to rise in intracellular Ca2+ and stimulation of PKC. Cytochalasin D, which disrupts the actin cytoskeleton, blocked ACPD-elicited chloride currents and ACPD-induced potentiation of NMDAR currents, consistent with a role for cytoskeletal protein(s) in the signaling pathway. As Group I mGluRs are localized to the perisynaptic region in juxtaposition to NMDARs at glutamatergic synapses, mGluR-mediated potentiation of NMDAR activity may play a role in synaptic transmission and plasticity including LTP.

Current Opinion in Neurobiology, 2001

Biochemical Society Transactions, 2009

NMDARs (N-methyl-D-aspartate receptors) are critical for synaptic function throughout the CNS (central nervous system). NMDAR-mediated Ca 2+ influx is implicated in neuronal differentiation, neuronal migration, synaptogenesis, structural remodelling, long-lasting forms of synaptic plasticity and higher cognitive functions. NMDAR-mediated Ca 2+ signalling in dendritic spines is not static, but can be remodelled in a cell-and synapse-specific manner by NMDAR subunit composition, protein kinases and neuronal activity during development and in response to sensory experience. Recent evidence indicates that Ca 2+ permeability of neuronal NMDARs, NMDARmediated Ca 2+ signalling in spines and induction of NMDAR-dependent LTP (long-term potentiation) at hippocampal Schaffer collateral-CA1 synapses are under control of the cAMP/ PKA (protein kinase A) signalling cascade. Thus, by enhancing Ca 2+ influx through NMDARs in spines, PKA can regulate the induction of LTP. An emerging concept is that activity-dependent regulation of NMDAR-mediated Ca 2+ signalling by PKA and by extracellular signals that modulate cAMP or protein phosphatases at synaptic sites provides a dynamic and potentially powerful mechanism for bi-directional regulation of synaptic efficacy and remodelling.

Journal of General Physiology, 2018

NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS). They are expressed throughout the CNS and play key physiological roles in synaptic function, such as synaptic plasticity, learning, and memory. NMDA receptors are also implicated in the pathophysiology of several CNS disorders and more recently have been identified as a locus for disease-associated genomic variation. NMDA receptors exist as a diverse array of subtypes formed by variation in assembly of seven subunits (GluN1, GluN2A-D, and GluN3A-B) into tetrameric receptor complexes. These NMDA receptor subtypes show unique structural features that account for their distinct functional and pharmacological properties allowing precise tuning of their physiological roles. Here, we review the relationship between NMDA receptor structure and function with an emphasis on emerging atomic resolution structures, which begin t...

Journal of Neuroscience, 2005

The NMDA receptor is an important subtype glutamate receptor that acts as a nonselective cation channel highly permeable to both calcium (Ca 2ϩ) and sodium (Na ϩ). The activation of NMDA receptors produces prolonged increases of intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i) and thereby triggers downstream signaling pathways involved in the regulation of many physiological and pathophysiological processes. Previous studies have focused on how Ca 2ϩ or Na ϩ affects NMDA receptor activity in isolation. Specifically, [Ca 2ϩ ] i increase may downregulate NMDA channels and thus is considered an important negative feedback mechanism controlling NMDA receptor activity, whereas an increase in intracellular Na ϩ concentration ([Na ϩ ] i) may upregulate NMDA channel activity. Thus so that the activity-dependent regulation of NMDA receptors and neuroplasticity may be further understood, a critical question that has to be answered is how an individual NMDA receptor may be regulated when both of these ionic species flow into neurons during the same time period via neighboring activated NMDA receptors. Here we report that the gating of a NMDA channel is regulated by the activation of remote NMDA receptors via a functional Na ϩ-Ca 2ϩ interaction and that during the activation of NMDA receptors Na ϩ influx potentiates Ca 2ϩ influx on one hand and overcomes Ca 2ϩ-induced inhibition of NMDA channel gating on the other hand. Furthermore, we have identified that a critical increase (5 Ϯ 1 mM) in [Na ϩ ] i is required to mask the effects of Ca 2ϩ on NMDA channel gating in cultured hippocampal neurons. Thus cross talk between NMDA receptors mediated by a functional Na ϩ-Ca 2ϩ interaction is a novel mechanism regulating NMDA receptor activity.

Current Pharmaceutical Design, 2007

A recent search on PubMed for the phrase NMDA receptor results in 2,190 hits on this topic for review articles and 20,100 hits for experimental papers. This is a direct reflection of the intensiveness, significance, and complexity associated with the research on this key receptor protein over the last several decades. In this review, we briefly describe the NMDA receptor structure, discuss the role of NMDA receptors in modulating synaptic plasticity and excitotoxicity, explore age-dependent changes in NMDA receptor functioning, and survey interesting NMDA receptor blockers. Given the huge existing literature on the subject, an exhaustive review has not been endeavored. Instead, an attempt was made to point out those studies that have been instrumental in the field or that are of special interest.

Molecular Brain Research, 2002

We report the cloning and characterization of a novel NMDA receptor subunit cDNA, which encodes a predicted polypeptide of 1003 amino acids. Phylogenic analysis indicates that this new subunit is most closely related to NR3A. Therefore, we term it NR3B. Important functional domains of glutamate receptors, such as the ligand-binding domain, the channel pore, and the channel gate, are conserved in NR3B. NR3B mRNA was expressed highly in pons, midbrain, medulla, and the spinal cord, but at low levels in the forebrain and the cerebellum. Although NR3A mRNA expression decreases sharply after the second postnatal weeks, NR3B mRNA expression levels in whole brain were constant during postnatal development and into adult. Coimmunoprecipitation analysis showed that NR3B could form NMDA receptor complex with NR1a and NR2A subunits in heterologous cells. Although expression of NR3B alone did not reconstitute 21 functional NMDA receptors, coexpression of NR3B reduced the Ca permeability of glutamate-induced currents in cells expressing NR1a and NR2A. These results indicate that NR3B is a dominant modulatory subunit that can modify the function of NMDA receptors. 21 Since high Ca permeability of NMDA receptors is thought to be a key feature for NMDA receptors to play critical roles in neurodevelopment, synaptic plasticity, and neuronal death, NR3B may contribute to the regulation of these physiological and pathological processes.

The Journal of Physiology, 1999

Science's STKE : signal transduction knowledge environment, 2004

Most excitatory synapses in the brain use the neurotransmitter glutamate to carry impulses between neurons. During fast transmission, glutamate usually activates a mixture of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the postsynaptic cell. Experimental scrutiny of NMDARs provides insight into their involvement in excitatory synaptic transmission and related processes such as as synaptic plasticity, neural development, and pain perception. There is increasing awareness that subtle variation in NMDAR properties is imparted by specific receptor subunits, and recent studies have started to provide perspective into some of the discrete tasks carried out by individual receptor subtypes.

The Journal of physiology, 1996

1. We have identified a new type of NMDA channel in rat central neurones that express mRNA for the NR2D subunit. We have examined single NMDA channels in cerebellar Purkinje cells (which possess NR1 and 2D), deep cerebellar nuclei (NR1, 2A, 2B and 2D) and spinal cord dorsal horn neurones (NR1, 2B and 2D). 2. In Purkinje cells, NMDA opened channels with a main conductance of 37.9 +/- 1.1 pS and a subconductance of 17.8 +/- 0.7 pS, with frequent transitions between the two levels. 3. NMDA activated low-conductance ('38/18 pS') events (along with high-conductance--'50/40 pS'--openings) in some patches from deep cerebellar nuclei and dorsal horn neurones. Our evidence suggests that 38/18 pS and 50/40 pS events arose from distinct types of NMDA receptors. 4. The transitions for 38/18 pS events were asymmetrical: steps from 38 to 18 pS were more frequent (72.2%) than steps from 18 to 38 pS. This feature appeared common to the 38/18 pS events in all three cell types, sugges...