Editing NMDA receptor (section)

== Gating ==
[[File:N1 N2 NMDA receptor.svg|thumb|400px|'''Figure 1:''' NR1/NR2 NMDA receptor]]
The NMDA receptor is a [[Glutamic acid|glutamate]] and [[ion channel]] protein receptor that is activated when [[glycine]] and glutamate bind to it.<ref name="Furukawa">{{cite journal | vauthors = Furukawa H, Singh SK, Mancusso R, Gouaux E | title = Subunit arrangement and function in NMDA receptors | journal = Nature | volume = 438 | issue = 7065 | pages = 185–192 | date = November 2005 | pmid = 16281028 | doi = 10.1038/nature04089 | s2cid = 4400777 | bibcode = 2005Natur.438..185F }}</ref> The receptor is a highly complex and dynamic heteromeric protein that interacts with a multitude of intracellular [[protein]]s via three distinct subunits, namely GluN1, GluN2, and GluN3. The GluN1 subunit, which is encoded by the GRIN1 gene, exhibits eight distinct isoforms owing to alternative splicing. On the other hand, the GluN2 subunit, of which there are four different types (A-D), as well as the GluN3 subunit, of which there are two types (A and B), are each encoded by six separate genes. This intricate molecular structure and genetic diversity enable the receptor to carry out a wide range of physiological functions within the [[nervous system]].<ref name="Loftis">{{cite journal | vauthors = Loftis JM, Janowsky A | title = The N-methyl-D-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications | journal = Pharmacology & Therapeutics | volume = 97 | issue = 1 | pages = 55–85 | date = January 2003 | pmid = 12493535 | doi = 10.1016/s0163-7258(02)00302-9 }}</ref><ref name="Kristiansen">{{cite journal | vauthors = Kristiansen LV, Huerta I, Beneyto M, Meador-Woodruff JH | title = NMDA receptors and schizophrenia | journal = Current Opinion in Pharmacology | volume = 7 | issue = 1 | pages = 48–55 | date = February 2007 | pmid = 17097347 | doi = 10.1016/j.coph.2006.08.013 }}</ref> All the subunits share a common membrane topology that is dominated by a large extracellular N-terminus, a membrane region comprising three transmembrane segments, a re-entrant pore loop, an extracellular loop between the transmembrane segments that are structurally not well known, and an intracellular C-terminus, which are different in size depending on the subunit and provide multiple sites of interaction with many intracellular proteins.<ref name="Loftis" /><ref name="Limapichat">{{cite journal | vauthors = Limapichat W, Yu WY, Branigan E, Lester HA, Dougherty DA | title = Key binding interactions for memantine in the NMDA receptor | journal = ACS Chemical Neuroscience | volume = 4 | issue = 2 | pages = 255–260 | date = February 2013 | pmid = 23421676 | pmc = 3751542 | doi = 10.1021/cn300180a }}</ref> Figure 1 shows a basic structure of GluN1/GluN2 subunits that forms the [[binding site]] for memantine, Mg<sup>2+</sup> and [[ketamine]].
[[File:NR1-NR2B subunit.png|thumb|270px|'''Figure 2:''' Transmembrane region of NR1 (left) and NR2B (right) subunits of NMDA receptor|left]]
Mg<sup>2+</sup> blocks the NMDA receptor channel in a voltage-dependent manner. The channels are also highly permeable to Ca<sup>2+</sup>. Activation of the receptor depends on glutamate binding, [[D-Serine|<small>D</small>-serine]] or glycine binding at its GluN1-linked binding site  and  [[AMPA receptor]]-mediated [[depolarization]] of the postsynaptic membrane, which relieves the voltage-dependent channel block by Mg<sup>2+</sup>. Activation and opening of the receptor channel thus allows the flow of K<sup>+</sup>, Na<sup>+</sup> and Ca<sup>2+</sup> ions, and the influx of Ca<sup>2+</sup> triggers intracellular signaling pathways.<ref name="Johnson" /><ref name="Maher">{{cite book | vauthors = Maher TJ | date = 2013 | chapter = Chapter 16: Anesthetic agents: General and local anesthetics. | chapter-url = https://downloads.lww.com/wolterskluwer_vitalstream_com/sample-content/9781609133450_Lemke/samples/Chapter_16.pdf | veditors = Lemke TL, Williams DA | title = Foye's Principles of Medicinal Chemistry | location = Philadelphia | publisher = Lippincott Williams & Wilkins | isbn = 978-1-60913-345-0 }}</ref> Allosteric receptor binding sites for zinc, proteins and the polyamines spermidine and spermine are also modulators for the NMDA receptor channels.<ref name="Danysz">{{cite journal | vauthors = Danysz W, Parsons CG | title = The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical evidence | journal = International Journal of Geriatric Psychiatry | volume = 18 | issue = Suppl 1 | pages = S23–S32 | date = September 2003 | pmid = 12973747 | doi = 10.1002/gps.938 | s2cid = 14852616 }}</ref>

The GluN2B subunit has been involved in modulating activity such as learning, memory, processing and feeding behaviors, as well as being implicated in number of human derangements. The basic structure and functions associated with the NMDA receptor can be attributed to the GluN2B subunit. For example, the glutamate binding site and the control of the Mg<sup>2+</sup> block are formed by the GluN2B subunit. The high affinity sites for glycine [[antagonist]] are also exclusively displayed by the GluN1/GluN2B receptor.<ref name="Kristiansen" />

GluN1/GluN2B transmembrane segments are considered to be the part of the receptor that forms the binding pockets for uncompetitive NMDA receptor antagonists, but the transmembrane segments structures are not fully known as stated above. It is claimed that three binding sites within the receptor, A644 on the GluNB subunit and A645 and N616 on the GluN1 subunit, are important for binding of memantine and related compounds as seen in figure 2.<ref name="Limapichat" />

The NMDA receptor forms a [[heterotetramer]] between two GluN1 and two GluN2 subunits (the subunits were previously denoted as GluN1 and GluN2), two obligatory GluN1 subunits and two regionally localized GluN2 subunits. A related [[gene]] family of GluN3 A and B subunits have an inhibitory effect on receptor activity. Multiple receptor [[isoform]]s with distinct brain distributions and functional properties arise by selective splicing of the GluN1 transcripts and differential expression of the GluN2 subunits.

Each receptor subunit has modular design and each structural module, also represents a functional unit:
* The ''[[extracellular]] [[Protein domain|domain]]'' contains two globular structures: a modulatory domain and a [[ligand]]-binding domain. GluN1 subunits bind the co-agonist glycine and GluN2 subunits bind the neurotransmitter glutamate.<ref name="Laube" /><ref name="Anson" />
* The ''agonist-binding module'' links to a membrane domain, which consists of three transmembrane 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 [[Electrical conductance|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 GluN1 and GluN3 subunits and the glutamate-binding module of the GluN2A 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.