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NMDA receptor

Function: - excitatory voltage-gated glutamate receptor/ion channel - transiently activated by nM concentrations of glutamate following depolarization of the postsynaptic membrane - depolarization attenuates voltage-dependent Mg+2 block of NMDA receptors - activity of the NMDA receptor is associated with long-term potentiation (LTP) & long-term depression (LTD) in the hippocampus [6,9,10] - LTP is dependent upon the NR2A subunit & LTD on the NR2B subunit - the NMDA receptor requires both glutamate & glycine for efficient gating - D-serine is a coagonist with glutamate at NMDA receptors [11] - Mg+2 blocks the NMDA receptor in a voltage-dependent manner, but potentiates NMDA-responses at positive membrane potentials - Na+, K+ & Ca+2 pass through the NMDA receptor channel & modulate the activity the receptor - Zn+2 blocks the NMDA current in a noncompetitive & voltage-independent manner - polyamines modulate glutamate-mediated responses - activity of NMDA receptors is sensitive to H+ ions - oxidation of a redox-modulated site inactivates the NMDA receptor. - tyrosine phosphorylation by src family proteins increases activity of the NMDA receptor Structure: - forms heteromeric channel of: 1) zeta subunit (GRIN1) 2) epsilon subunit (GRIN2A, GRIN2B, GRIN2C or GRIN2D) 3) third subunit (GRIN3A or GRIN3B) Compartment: - excitatory glutamate receptors in the CNS are predominantly dendritic [5], embedded within the postsynaptic density Expression: - present throughout the brain & spinal cord - consistently present in excitatory synapses of the forebrain Pharmacology: - memantine (Namenda) is a low-moderate affinity NMDA receptor antagonist FDA approved in 2003 for moderate to advanced Alzheimer's disease. Pathology: - anti-NMDA receptor antibodies associated with anti-NMDA receptor encephalitis

Interactions

molecular events

Related

anti-NMDA receptor encephalitis; NMDAR Ab encephalitis long term potentiation (LTP) memantine (Auzura, Namenda, Exiba, Akatinol) NMDA receptor antagonist NMDA receptor-regulated protein 1; N-alpha-acetyltransferase 15, natA auxiliary subunit; gastric cancer antigen Ga19; N-terminal acetyltransferase; protein tubedown-1; Tbdn100 (NAA15, GA19, NARG1, NATH, TBDN100)

General

ionotropic glutamate receptor Na+ channel phosphoprotein voltage-dependent Ca+2 channel

Figures/Diagrams

Physiologic Activators of Apoptosis

Properties

COMPARTMENT: postsynaptic density CELL-REGION: dendritic spine CELL: neuron MOTIF: ligand-binding site membrane region ion channel COMPARTMENT: cellular membrane MOTIF: membrane region phosphorylation site ION-PERMEABILITY: Ca+2 Na+ K+ SUBUNITS: glutamate receptor epsilon MOTIF: exoplasmic domain {N-TERMINAL} MOTIF: glycosylation site cysteine residue {N_TERMINAL} MODIFICATION: cysteine residue {N_TERMINAL} cysteine residue {N_TERMINAL} MODIFICATION: cysteine residue {N_TERMINAL} ligand-binding site transmembrane domain {TM1} cytoplasmic loop MOTIF: allosteric site FOR-BINDING-OF: polyamine LOOP#: 1 transmembrane domain {TM2} MOTIF: Mg+2-binding site exoplasmic loop MOTIF: allosteric site FOR-BINDING-OF: glycine LOOP#: 1 transmembrane domain {TM3} cytoplasmic domain {C-TERMINAL} MOTIF: S/T phosphorylation site Tyr phosphorylation site PDZ recognition motif NAME: PDZ recognition motif SITE: C_terminus FOR-BINDING-VIA: PDZ domain glutamate receptor zeta MOTIF: exoplasmic domain {N-TERMINAL} MOTIF: glycosylation site cysteine residue {N_TERMINAL} MODIFICATION: cysteine residue {N_TERMINAL} cysteine residue {N_TERMINAL} MODIFICATION: cysteine residue {N_TERMINAL} ligand-binding site SITE: N-TERMINAL transmembrane domain {TM1} cytoplasmic loop MOTIF: allosteric site SITE: cytoplasmic loop-1 FOR-BINDING-OF: polyamine LOOP#: 1 transmembrane domain {TM2} MOTIF: Mg+2-binding site exoplasmic loop MOTIF: allosteric site SITE: exoplasmic loop-1 FOR-BINDING-OF: glycine transmembrane domain {TM3} cytoplasmic domain {C-TERMINAL} MOTIF: Ser phosphorylation site {L3-1} Thr phosphorylation site {L3-2} Ser phosphorylation site {L3-3} Thr phosphorylation site {L3-4} Ser phosphorylation site {L3-5} Ser phosphorylation site {L3-6} Thr phosphorylation site {L3-7} Ser phosphorylation site {L3-8} hydrophobic region glutamate [NMDA] receptor subunit 3A MOTIF: exoplasmic domain {1-674} MOTIF: signal sequence {1-23} N-glycosylation site {N145} N-glycosylation site {N264} N-glycosylation site {N275} N-glycosylation site {N285} N-glycosylation site {N296} N-glycosylation site {N426} N-glycosylation site {N439} N-glycosylation site {N549} N-glycosylation site {N565} transmembrane domain {675-695} cytoplasmic loop {696-748} transmembrane domain {749-769} exoplasmic loop {770-930} MOTIF: N-glycosylation site {N886} transmembrane domain {931-951} PPP2CB binding site {951-987} cytoplasmic domain {952-1115} MOTIF: coiled coil {1058-1109} NMDA receptor-associated protein 1 MOTIF: proline-rich region SITE: 15-139 MOTIF: proline residue (SEVERAL) transmembrane domain {165-185} transmembrane domain {197-217} transmembrane domain {228-248} transmembrane domain {253-273} transmembrane domain {283-303} transmembrane domain {307-327} transmembrane domain {346-366} MISC-INFO: CONDUCTANCE 50 PS Kd [glutamate] HIGH LIGAND = ASPARTATE LIGAND = HOMOCYSTEATE LIGAND = QUINOLINIC_ACID Kd [glycine] 1 MM INHIBITOR = 2_AMINO_5_PHOSPHONOVALERATE INHIBITOR = 2_AMINO_5_PHOSPHONOHEPTANOATE INHIBITOR = PHENCYCLIDINE INHIBITOR = MK_801 INHIBITOR = KETAMINE INHIBITOR = MG+2 INHIBITOR = ZN+2

References

  1. Choi 1988
  2. Aizenman E, Hartnett KA, Reynolds IJ. Oxygen free radicals regulate NMDA receptor function via a redox modulatory site. Neuron. 1990 Dec;5(6):841-6. PMID: 2148489
  3. Ben-Ari Y, Aniksztejn L, Bregestovski P. Protein kinase C modulation of NMDA currents: an important link for LTP induction. Trends Neurosci. 1992 Sep;15(9):333-9. Review. PMID: 1382331
  4. Barnard EA. Receptor classes and the transmitter-gated ion channels. Trends Biochem Sci. 1992 Oct;17(10):368-74. Review. PMID: 1360717
  5. Ikegaya Y, Kim JA, Baba M, Iwatsubo T, Nishiyama N, Matsuki N. Rapid and reversible changes in dendrite morphology and synaptic efficacy following NMDA receptor activation: implication for a cellular defense against excitotoxicity. J Cell Sci. 2001 Nov;114(Pt 22):4083-93. PMID: 11739640
  6. Villarreal DM, Do V, Haddad E, Derrick BE. NMDA receptor antagonists sustain LTP and spatial memory: active processes mediate LTP decay. Nat Neurosci. 2002 Jan;5(1):48-52. PMID: 11740500
  7. Sheng M. Molecular organization of the postsynaptic specialization. Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7058-61. Review. PMID: 11416187
  8. Yaka R, Thornton C, Vagts AJ, Phamluong K, Bonci A, Ron D. NMDA receptor function is regulated by the inhibitory scaffolding protein, RACK1. Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5710-5. Epub 2002 Apr 9. PMID: 11943848
  9. Liu L, Wong TP, Pozza MF, Lingenhoehl K, Wang Y, Sheng M, Auberson YP, Wang YT. Role of NMDA Receptor Subtypes in Governing the Direction of Hippocampal Synaptic Plasticity. Science. 2004 May 14;304(5673):1021-4. PMID: 15143284
  10. Bliss T, Schoepfer R. NEUROSCIENCE: Controlling the Ups and Downs of Synaptic Strength. Science. 2004 May 14;304(5673):973-4. PMID: 15143268
  11. UniProt :accession Q9GZT4
  12. Wikipedia; Note: NMDA receptor entry http://en.wikipedia.org/wiki/NMDA_receptor
  13. Dalmau J, Gleichman AJ, Hughes EG et al Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008 Dec;7(12):1091-8 PMID: 18851928

Components

glutamate receptor epsilon or glutamate receptor, ionotropic NMDA 2 (GRIN2) glutamate receptor zeta glutamate [NMDA] receptor subunit 3A; N-methyl-D-aspartate receptor subtype (NR3A, NMDAR-L, GRIN3A) NMDA receptor-associated protein 1; NMDA receptor glutamate-binding subunit; MAPK-activating protein PM02 (GRINA, NMDARA1)