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NMDA receptor



   

 

glutamate receptor, ionotropic, N-methyl D-aspartate 1
Identifiers
Symbol GRIN1
Alt. Symbols NMDAR1
Entrez 2902
HUGO 4584
OMIM 138249
RefSeq NM_021569
UniProt Q05586
Other data
Locus Chr. 9 q34.3
glutamate receptor, ionotropic, N-methyl D-aspartate 2A
Identifiers
Symbol GRIN2A
Alt. Symbols NMDAR2A
Entrez 2903
HUGO 4585
OMIM 138253
RefSeq NM_000833
UniProt Q12879
Other data
Locus Chr. 16 p13.2
glutamate receptor, ionotropic, N-methyl D-aspartate 2B
Identifiers
Symbol GRIN2B
Alt. Symbols NMDAR2B
Entrez 2904
HUGO 4586
OMIM 138252
RefSeq NM_000834
UniProt Q13224
Other data
Locus Chr. 12 p12
glutamate receptor, ionotropic, N-methyl D-aspartate 2C
Identifiers
Symbol GRIN2C
Alt. Symbols NMDAR2C
Entrez 2905
HUGO 4587
OMIM 138254
RefSeq NM_000835
UniProt Q14957
Other data
Locus Chr. 17 q24-q25
glutamate receptor, ionotropic, N-methyl D-aspartate 2D
Identifiers
Symbol GRIN2D
Alt. Symbols NMDAR2D
Entrez 2906
HUGO 4588
OMIM 602717
RefSeq NM_000836
UniProt O15399
Other data
Locus Chr. 19 q13.1-qter

The NMDA receptor (NMDAR) is an ionotropic receptor for glutamate (NMDA (N-methyl D-aspartate) is a name of its selective specific agonist). Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations. This allows flow of Na+ and small amounts of Ca2+ ions into the cell and K+ out of the cell.

Calcium flux through NMDARs is thought to play a critical role in synaptic plasticity, a cellular mechanism for learning and memory. The NMDA receptor is distinct in that it is both ligand-gated and voltage-dependent.

Additional recommended knowledge

Contents

Structure

The NMDA receptor forms a heterodimer between NR1 and NR2 subunits, which explains why NMDA receptors contain two obligatory NR1 subunits and two regionally localized NR2 subunits.[2] A related gene family of NR3 A and B subunits have an inhibitory effect on receptor activity. Multiple receptor isoforms with distinct brain distributions and functional properties arise by selective splicing of the NR1 transcripts and differential expression of the NR2 subunits.

Each receptor subunit has modular design and each structural module also represents a functional unit:

  • The extracellular domain contains two globular structures: a modulatory domain and a ligand binding domain. NR1 subunits bind the co-agonist glycine and NR2 subunits bind the neurotransmitter glutamate.
  • The agonist-binding module links to a membrane domain, which consists of three trans-membrane segments and a re-entrant loop reminiscent of the selectivity filter of potassium channels.
  • The membrane domain contributes residues to the channel pore and is responsible for the receptor's high-unitary conductance, high-calcium permeability, and voltage-dependent magnesium block.
  • Each subunit has an extensive cytoplasmic domain, which contain residues that can be directly modified by a series of protein kinases and protein phosphatases, as well as residues that interact with a large number of structural, adaptor, and scaffolding proteins.

The glycine-binding module of the NR1 subunit and the glutamate-binding module of the NR2A subunit have been expressed as soluble proteins, and their three-dimensional structure has been solved at atomic resolution by x-ray crystallography. This has revealed a common fold with amino acid-binding bacterial proteins and with the glutamate-binding module of AMPA-receptors and kainate-receptors.

Variants

NR1

There are eight variants of the NR1 subunit produced by alternative splicing of GRIN1:[3]

  • NR1-1a, NR1-1b; NR1-1a is the most abundantly expressed form.
  • NR1-2a, NR1-2b;
  • NR1-3a, NR1-3b;
  • NR1-4a, NR1-4b;

NR2

Various isoforms of NR2 subunits exist, and are referred to with the nomenclature NR2A through D (GRIN2A, GRIN2B, GRIN2C, GRIN2D). They contain the binding-site for the neurotransmitter glutamate. Unlike NR1 subunits, NR2 subunits are expressed differentially across various cell types and control the electrophysiological properties of the NMDA receptor. One particular subunit, NR2B, is mainly present in immature neurons and in extrasynaptic locations, and contains the binding-site for the selective inhibitor ifenprodil.

Whereas NR2B is predominant in the early postnatal brain, the number of NR2A subunits grows, and eventually NR2A subunits outnumber NR2B. This is called NR2B-NR2A developmental switch, and is notable because of the different kinetics each NR2 subunit lends to the receptor.[4] There are three hypothetic models to describe this switch mechanism:

  • Dramatic increase in synaptic NR2A along with decrease in NR2B
  • Extrasynaptic displacement of NR2B away from the synapse with increase in NR2A
  • Increase of NR2A diluting the number of NR2B without the decrease of the former.

The NR2B and NR2A subunits also have differential roles in mediating excitotoxic neuronal death.[5] The developmental switch in subunit composition is thought to explain the developmental changes in NMDA neurotoxicity.[6] Disruption of the gene for NR2B in mice causes perinatal lethality, whereas the disruption of NR2A gene produces viable mice, although with impaired hippocampal plasticity.

Agonists

Activation of NMDA receptors requires binding of glutamate or aspartate (aspartate does not stimulate the receptors as strongly.[7]) In addition, NMDARs also require the binding of the co-agonist glycine for the efficient opening of the ion channel, which is a part of this receptor.

D-serine has also been found to co-agonize the NMDA receptor with even greater potency than glycine. D-serine is produced by serine racemase in astrocyte cells, and is enriched in the same areas as NMDA receptors. Removal of D-serine can block NMDA-mediated excitatory neurotransmission in many areas. Recently, it has been shown that D-serine is also synthesized in neurons, indicating a role for neuron-derived D-serine in NMDA receptor regulation.

In addition, a third requirement is membrane depolarization. A positive change in transmembrane potential will make it more likely that the ion channel in the NMDA receptor will open by expelling the Mg2+ ion that blocks the channel from the outside. This property is fundamental to the role of the NMDA receptor in memory and learning, and it has been suggested that this channel is a biochemical substrate of Hebbian learning, where it can act as a coincidence detector for membrane depolarization and synaptic transmission.

Antagonists

NMDA Receptor Antagonists are used as anesthetics for animals and sometimes humans, and are often used as recreational drugs because of their hallucinogenic properties. When NMDA Receptor Antagonists are given to rodents in large doses, they can cause a form of brain damage called Olney's Lesions. However, there are fundamental differences between human and rodent brains. For now there is not enough research to show that large doses of NMDA antagonists cause Olney's Lesions in humans or monkeys.[8]

Common NMDA Receptor Antagonists include:

Modulators

The NMDA receptor is modulated by a number of endogenous and exogenous compounds:

  • Mg2+ not only blocks the NMDA channel in a voltage-dependent manner but also potentiates NMDA-induced responses at positive membrane potentials. Magnesium treatment has been used to produce rapid recovery from depression.[11]
  • Na+, K+ and Ca2+ not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors.
  • Zn2+ blocks the NMDA current in a noncompetitive and a voltage-independent manner.
  • It has been demonstrated that polyamines do not directly activate NMDA receptors, but instead act to potentiate or inhibit glutamate-mediated responses.
  • Aminoglycosides have been shown to have a similar effect to polyamines, and this may explain their neurotoxic effect.
  • The activity of NMDA receptors is also strikingly sensitive to the changes in H+ concentration, and partially inhibited by the ambient concentration of H+ under physiological conditions. The level of inhibition by H+ is greaty reduced in receptors containing the NR1a subtype, which contains the positively-charged insert Exon 5. The effect of this insert may be mimicked by positively-charged polyamines and aminoglycosides, explaining their mode of action.
  • NMDA receptor function is also strongly regulated by chemical reduction and oxidation, via the so-called "redox modulatory site." Through this site, reductants dramatically enhance NMDA channel activity, whereas oxidants either reverse the effects of reductants or depress native responses. It is generally believed that NMDA receptors are modulated by endogenous redox agents such as glutathione, lipoic acid, and the essential nutrient pyrroloquinoline quinone.[12]

Role

This channel complex contributes to excitatory synaptic transmission as well as synaptic plasticity at sites throughout the brain and the spinal cord, and is modulated by a number of endogenous and exogenous compounds. NMDA receptors play a key role in a wide range of physiologic and pathologic processes. The role of the NMDA receptor in general, with regard to syanptic plasicity, can be described as coincidence detection.

See also

References

  1. ^ Laube, B; Hirai H, Sturgess M, Betz H, and Kuhse J (1997). "Molecular determinants of agonist discrimination by NMDA receptor subunits: Analysis of the glutamate binding site on the NR2B subunit". Neuron 18 (3): 493-503. PMID 9115742. Retrieved on 2007-01-17.
  2. ^ Stephenson FA (2006 Nov). "Structure and trafficking of NMDA and GABAA receptors". Biochem Soc Trans. 34: 877-81. doi:10.1042/BST0340877.
  3. ^ Stephenson FA. (2006) Structure and trafficking of NMDA and GABAA receptors. Biochem Soc Trans. 2006 Nov;34 (Pt 5):877-81. PMID 17052219 free fulltext pdf
  4. ^ a b Liu XB, Murray KD, Jones EG.(2004) Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development. The Journal of Neuroscience, 24(40):8885-95.PMID 15470155free fulltext
  5. ^ Y. Liu, T. P. Wong, M. Aarts, A. Rooyakkers, L. Liu, T. W. Lai, D. C. Wu, J. Lu, M. Tymianski, A. M. Craig, and Y. T. Wang (2007) NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death Both In Vitro and In Vivo J. Neurosci., March 14, 2007; 27(11): 2846 - 2857. PMID 17360906
  6. ^ Miou Zhou, Michel Baudry (2006) Developmental Changes in NMDA Neurotoxicity Reflect Developmental changes in Subunit Composition of NMDA ReceptorsThe Journal of Neuroscience, March 15, 2006, 26(11):2956-2963; doi:10.1523/JNEUROSCI.4299-05.2006 PMID 16540573 free fulltext
  7. ^ Philip E. Chen, Matthew T. Geballe, Phillip J. Stansfeld, Alexander R. Johnston, Hongjie Yuan, Amanda L. Jacob, James P. Snyder, Stephen F. Traynelis, and David J. A. Wyllie. 2005. Structural Features of the Glutamate Binding Site in Recombinant NR1/NR2A N-Methyl-D-aspartate Receptors Determined by Site-Directed Mutagenesis and Molecular Modeling. Molecular Pharmacology. Volume 67, Pages 1470-1484.
  8. ^ Anderson C. "The Bad News Isn't In: A Look at Evidence for Specific Mechanisms of Dissociative-Induced Brain Damage and Cognitive Impairment". Erowid.org, June 2003
  9. ^ "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy", University Health Network, Toronto, September 2005
  10. ^ Popik P, Layer RT, Skolnick P (1994): "The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex." Psychopharmacology (Berl), 114(4), 672-4. Abstract
  11. ^ Eby GA, Eby KL. (2006) Rapid recovery from major depression using magnesium treatment. Med Hypotheses. 2006;67(2):362-70 PMID 16542786
  12. ^ Aizenman, E., S.A. Lipton and R.H. Loring. Selective modulation of NMDA induced responses by reduction and oxidation. Neuron 1989;2:1257-1263.
  • Dingledine R, Borges K, Bowie D, Traynelis SF (1999). "The glutamate receptor ion channels". Pharmacol. Rev. 51 (1): 7-61. PMID 10049997.
  • NMDA receptor pharmacology
  • Motor Discoordination Results from Combined Gene Disruption of the NMDA Receptor NR2A and NR2C Subunits, But Not from Single Disruption of the NR2A or NR2C Subunit
  • A schematic diagram summarizes three potential models for the switching of NR2A and NR2B subunits at developing synapses. - a figure from Liu et al., 2004[4]
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "NMDA_receptor". A list of authors is available in Wikipedia.
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