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Stylised depiction of an activated NMDAR. Glutamate is in the glutamate binding site and glycine is in the glycine binding site. Allosteric sites that would cause inhibition of the receptor are not occupied. NMDARs require the binding of two molecules of glutamate or aspartate and two of glycine.[1]

The NMDA receptor (NMDAR), a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function.[2]

The NMDAR is a specific type of ionotropic glutamate receptor. NMDA (N-methyl D-aspartate) is the name of a selective agonist that binds to NMDA receptors but not to other glutamate receptors. Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations. A unique property of the NMDA receptor is its voltage-dependent activation, a result of ion channel block by extracellular Mg2+ ions. This allows voltage-dependent flow of Na+ and small amounts of Ca2+ ions into the cell and K+ out of the cell.[3][4][5][6]

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 two ways: First, it is both ligand-gated and voltage-dependent; second, it requires co-activation by two ligands - glutamate and glycine.

Contents

Structure

The NMDA receptor forms a heterotetramer between two NR1 and two NR2 subunits, which explains why NMDA receptors contain two obligatory NR1 subunits and two regionally localized NR2 subunits. 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 modules of the NR1 and NR3 subunits 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:[7]

  • 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

NR2 subunit in vertebrates (left) and invertebrates (right). Ryan et al., 2008

While a single NR2 subunit is found in invertebrate organisms, four distinct isoforms of the NR2 subunit have been formed by gene duplication in vertebrates, 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.[8]

There are three hypothetical 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.[9] The developmental switch in subunit composition is thought to explain the developmental changes in NMDA neurotoxicity.[10] 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. One study suggests that reelin may play a role in the NMDA receptor maturation by increasing the NR2B subunit mobility.[11]

Ligands

Agonists

Activation of NMDA receptors requires binding of glutamate or aspartate (aspartate does not stimulate the receptors as strongly).[12] 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, 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 synthesized mostly by 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

Antagonists of the NMDA receptor are used as anesthetics for animals and sometimes humans, and are often used as recreational drugs due to their hallucinogenic properties, in addition to their unique effects at elevated dosages such as dissociation. 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, and, so far, the published research on Olney's Lesions is inconclusive in its occurrence upon human or monkey brain tissues with respect to an increase in the presence of NMDA receptor antagonists.[13]

Common NMDA receptor antagonists include:

Modulators

The NMDA receptor is modulated by a number of endogenous and exogenous compounds:[15]

  • Mg2+ not only blocks the NMDA channel in a voltage-dependent manner but also potentiates NMDA-induced responses at positive membrane potentials. Magnesium glycinate and magnesium taurinate treatment has been used to produce rapid recovery from depression.[16]
  • 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 greatly 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.[17]

Functional role

The NMDA receptor is a non-specific cation channel and, thus, directly contributes to excitatory synaptic transmission by depolarizing the postsynaptic cell. With regard to synaptic plasticity, the role of the NMDA receptor is best described as coincidence detection: only if both the pre- and postsynaptic cells are simultaneously active will NMDA receptors become unblocked and allow calcium ions to enter the postsynaptic cell. Thus, the NMDA receptor converts an electrical signal into a biochemical signal that can trigger synaptic plasticity. NMDA receptors are modulated by a number of endogenous and exogenous compounds and play a key role in a wide range of physiologic and pathologic processes, such as excitotoxicity.

Clinical significance

Recently, NMDARs were associated with a rare autoimmune disease, Anti-NMDAR encephalitis, that usually occurs due to cross reactivity of antibodies produced by the immune system against ectopic brain tissues, such as those found in teratoma.[22]

See also

External links

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. doi:10.1016/S0896-6273(00)81249-0. PMID 9115742.  
  2. ^ Clinical Implications of Basic Research: Memory and the NMDA receptors, Fei Li and Joe Z. Tsien, N Engl J Med, 361:302, July 16, 2009
  3. ^ Dingledine R, Borges K, Bowie D, Traynelis SF (March 1999). "The glutamate receptor ion channels". Pharmacol. Rev. 51 (1): 7–61. PMID 10049997. http://pharmrev.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10049997.  
  4. ^ Liu Y, Zhang J (October 2000). "Recent development in NMDA receptors". Chin. Med. J. 113 (10): 948–56. PMID 11775847. http://www.cmj.org/Periodical/LinkIn.asp?journal=Chinese%20Medical%20Journal&linkintype=pubmed&year=2000&vol=113&issue=10&beginpage=948.  
  5. ^ Cull-Candy S, Brickley S, Farrant M (June 2001). "NMDA receptor subunits: diversity, development and disease". Curr. Opin. Neurobiol. 11 (3): 327–35. doi:10.1016/S0959-4388(00)00215-4. PMID 11399431. http://linkinghub.elsevier.com/retrieve/pii/S0959-4388(00)00215-4.  
  6. ^ Paoletti P, Neyton J (February 2007). "NMDA receptor subunits: function and pharmacology". Curr Opin Pharmacol 7 (1): 39–47. doi:10.1016/j.coph.2006.08.011. PMID 17088105.  
  7. ^ Stephenson FA (November 2006). "Structure and trafficking of NMDA and GABAA receptors". Biochem. Soc. Trans. 34 (Pt 5): 877–81. doi:10.1042/BST0340877. PMID 17052219. http://www.biochemsoctrans.org/bst/034/0877/0340877.pdf.  
  8. ^ Liu XB, Murray KD, Jones EG (October 2004). "Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development". J. Neurosci. 24 (40): 8885–95. doi:10.1523/JNEUROSCI.2476-04.2004. PMID 15470155.  
  9. ^ Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J, Tymianski M, Craig AM, Wang YT (March 2007). "NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo". J. Neurosci. 27 (11): 2846–57. doi:10.1523/JNEUROSCI.0116-07.2007. PMID 17360906.  
  10. ^ Zhou M, Baudry M (March 2006). "Developmental changes in NMDA neurotoxicity reflect developmental changes in subunit composition of NMDA receptors". J. Neurosci. 26 (11): 2956–63. doi:10.1523/JNEUROSCI.4299-05.2006. PMID 16540573.  
  11. ^ Groc L, Choquet D, Stephenson FA, Verrier D, Manzoni OJ, Chavis P (2007). "NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin". J. Neurosci. 27 (38): 10165–75. doi:10.1523/JNEUROSCI.1772-07.2007. PMID 17881522.  
  12. ^ Chen PE, Geballe MT, Stansfeld PJ, Johnston AR, Yuan H, Jacob AL, Snyder JP, Traynelis SF, Wyllie DJ (May 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". Mol. Pharmacol. 67 (5): 1470–84. doi:10.1124/mol.104.008185. PMID 15703381.  
  13. ^ Anderson C (2003-06-01). "The Bad News Isn't In : A Look at Dissociative-Induced Brain Damage and Cognitive Impairment". Erowid DXM Vaults : Health. http://www.erowid.org/chemicals/dxm/dxm_health2.shtml. Retrieved 2008-12-17.  
  14. ^ "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy". ClinicalTrials.gov. 2005-09-01. http://www.clinicaltrials.gov/ct/show/NCT00188383?order=4. Retrieved 2008-12-17.  
  15. ^ Huggins DJ, Grant GH (January 2005). "The function of the amino terminal domain in NMDA receptor modulation". J. Mol. Graph. Model. 23 (4): 381–8. doi:10.1016/j.jmgm.2004.11.006. PMID 15670959.  
  16. ^ Eby GA, Eby KL (2006). "Rapid recovery from major depression using magnesium treatment". Medical hypotheses 67 (2): 362–70. doi:10.1016/j.mehy.2006.01.047. PMID 16542786.  
  17. ^ Aizenman E, Lipton SA, Loring RH (March 1989). "Selective modulation of NMDA responses by reduction and oxidation". Neuron 2 (3): 1257–63. doi:10.1016/0896-6273(89)90310-3. PMID 2696504.  
  18. ^ Yu XM, Askalan R, Keil GJ, Salter MW (January 1997). "NMDA channel regulation by channel-associated protein tyrosine kinase Src". Science (journal) 275 (5300): 674–8. doi:10.1126/science.275.5300.674. PMID 9005855.  
  19. ^ Chen Y, Beffert U, Ertunc M, Tang TS, Kavalali ET, Bezprozvanny I, Herz J (September 2005). "Reelin modulates NMDA receptor activity in cortical neurons". J. Neurosci. 25 (36): 8209–16. doi:10.1523/JNEUROSCI.1951-05.2005. PMID 16148228. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=16148228.  
  20. ^ Hawasli AH, Benavides DR, Nguyen C, Kansy JW, Hayashi K, Chambon P, Greengard P, Powell CM, Cooper DC, Bibb JA (July 2007). "Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation". Nat. Neurosci. 10 (7): 880–6. doi:10.1038/nn1914. PMID 17529984. http://dx.doi.org/10.1038/nn1914.  
  21. ^ Zhang S, Edelmann L, Liu J, Crandall JE, Morabito MA (January 2008). "Cdk5 regulates the phosphorylation of tyrosine 1472 NR2B and the surface expression of NMDA receptors". J. Neurosci. 28 (2): 415–24. doi:10.1523/JNEUROSCI.1900-07.2008. PMID 18184784. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=18184784.  
  22. ^ Iizuka T, Sakai F (September 2008). "[Anti-nMDA receptor encephalitis--clinical manifestations and pathophysiology]" (in Japanese). Brain Nerve 60 (9): 1047–60. PMID 18807939.  
  23. ^ 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







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