ligand binding domain

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Ligand Binding Domain - the Venus Fly Trap

The large N-terminal domain of the mGlu receptor contains the ligand binding site, which isformed by two hinged globular domains - the so-called Venus Flytrap Domain (VFD). Binding ofglutamate causes the two domains to close, providing the structural change in the TMD thattriggers intracellular G-protein activation. Interestingly, it has been reported that the binding of

agonist to one VFD is able to activate not only the G-proteins associated with it's own TMD, butalso those associated with it's partner subunit, (cis- and trans-activation, respectively;Brock et al2007), though only a single subunit may be activated at a time. In this context, it is interesting thatstrong negative cooperativity between the individual binding sites exists (Suzuki et al 2004), thuspresumably ensuring that only one binding site is occupied.

Ionotropic receptors

There are three types of ion channel receptor, named after chemicals that specifically interactwith them - NMDA, AMPA and Kainatereceptors. All the ion channel receptors have a similarstructure. They are built from assemblies of four separate proteins (subunits) that make a channel

or pore through the membrane. It is through this pore that ions can pass. The subunitsthemselves come in different variants. For instance, the NMDA receptor (NMDAR) is built fromGluN1 subunits (required) as well as subunits chosen from GluN2A, B,C or D. Thus the receptorcomposition can be GluN1:GluN2A, GluN1:GluN2B, GluN1:GluN2AB ... etc. In addition, thesubunits come in multiple forms - so the number of possible combinations of individual subunits isastronomical! Each combination of receptor subunits can bring subtle variations in the propertiesof those receptors and so although we may talk about 'the NMDA receptor', what we really meanis a family of receptors that may react differently to the same signal in different neurons and/or atdifferent stages in development.

Metabotropic Receptors

In addition, there is another group of glutamate receptors that are not ion channels, but pass

signals into the cell via other accessory proteins (G-proteins). These receptors are termedthe metabotropic glutamate receptors. There are several families of such receptors (alsotermed G-protein coupled receptors or GPCRs) and the metabotropic glutamatereceptors (mGluRs) belong to a family that also includes taste receptors and several hormonereceptors that are distinct from the prototypical family that contains receptors such as thedopamine receptors, muscarinic receptors and rhodopsin. One of the main distinguishingfeatures is the Venus Flytrap Domain (VFD) that forms the binding site for theneurotransmitter(or hormone ... or whatever you are tasting!). This domain is found atthe externalface of the plasma membrane. As the name suggests, it acts like a venusflytrap, closing once the right molecule has entered and latched onto its binding site. Thisin turn changes the shape of the rest of the protein, triggering the release of the G-

proteins that are bound to the receptor on the internal face of the membrane. The release ofthe G-protein initiates a signaling cascade that results in functional changes inside the cell. Thus

the binding of glutamate to the outside of the neuron affects what happens inside thatneuron, but in an indirect manner.

The signaling cascades activated by these receptors can be very long and complex and so theresulting changes in function are relatively slow. Thus, mGluRs are not involved directly inneurotransmission - that is the domain of the ionotropic receptors (iGluRs). However, the mGluRsregulate the operation of the iGluRs - they are involved in determining how many iGluR receptorsare present in the post-synaptic part of the synapse and in how well they allow ions through theirchannels. In this way, they can determine how strong the response is to a given signal, acting like
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a volume or gain control on an amplifier. They are also found in the pre-synaptic elements of thesynapse where they can determine how much neurotransmitter is released into the synaptic cleftand so affecting the size of the initial signal as well. Interestingly, this means that the mGluRs canregulate the release of neurotransmitters other that glutamate ... indeed they have been shown toregulate the release of dopamine (important in the reward systems in the brain and in the controlof complex movement) and ofGABA, the major inhibitory neurotransmitter.

Several types of ionotropic glutamate receptors have been identified. Three of these are ligand-gated ion channels called NMDAreceptors, AMPA receptors, and kainate receptors.Theseglutamate receptorsare named after the agonists that activate them: NMDA (N-methyl-D-aspartate), AMPA (-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate), and kainic acid. All ofthe ionotropic glutamate receptorsare nonselective cation channels, allowing the passageofNa+ and K+, and in some cases small amounts of Ca2+. Like nAChreceptors,the postsynapticcurrents produced have a reversal potentialclose to 0 mV; hence AMPA,kainate, and NMDAreceptoractivationalways produces excitatory postsynapticresponses. And,like other ligand-gated channel receptors, AMPA/kainate and NMDA receptors are formed fromthe association of several protein subunits that can combine in many ways to produce a largenumber ofreceptorisoforms.The NMDA subfamily of glutamate receptors also form multisubunit,nonselective cation channels similar to most other ligand-gated ion channelreceptors.Thesereceptors, however, have especially interesting properties. Perhaps most significant is thefact that NMDAreceptorion channelsallow the entry of Ca2+ in addition to monovalent cationssuch as Na+ and K+. As a result, EPSPs produced by NMDAreceptorscan increase theconcentration of Ca2+ within the postsynapticneuron; the Ca2+ concentration change can then actas a second messenger to activate intracellular signaling cascades Other unique properties ofNMDA receptors are that opening the channel requires the presence of a co-agonist (the aminoacid glycine), and that extracellular Mg2+ blocks the channel at hyperpolarized, but notdepolarized, voltages. Hence, NMDA receptorsallow the passage of cations only when theMg2+ block is removed by the depolarizationof thepostsynaptic cell, either by a large number ofexcitatoryinputsor by the repetitive firing of thepresynapticcell. These properties are widelythought to be the basis for some forms of information storage at synapses, as describedinChapter 25. There are at least five forms of NMDA receptorsubunits (NMDA-R1, and NMDA-R2A through NMDA-R2D); differentsynapses have distinct combinations of these subunits,producing a variety of NMDAreceptor-mediatedpostsynaptic responses.

While some glutamatergic synapses have only AMPA or only NMDA receptors, most have bothAMPA and NMDA receptors. An antagonist of NMDA receptors, APV (2-amino-5-phosphono-valerate), is often used to differentiate between the tworeceptortypes. The use of this drug hasalso revealed differences between the EPSPs produced by NMDA and those produced byAMPA/kainate receptors, such as the fact that the synaptic currents produced byNMDA receptors are slower and longer-lasting than the those produced byIn addition to these ionotropic glutamate receptors, there are three types of metabotropicglutamate receptor(mGluRs). These receptors, which modulatepostsynapticionchannels indirectly, differ in their coupling to intracellular messengersand in their sensitivity topharmacological agents. Activationof many of these receptors leads to inhibitionofpostsynaptic Ca2+ and Na+ channels. Unlike the excitatory ionotropic glutamatereceptors,mGluRs cause slowerpostsynaptic responses that can either increase or decrease the

excitability ofpostsynaptic cells. Hence the physiological roles of mGluRs are quite varied.

GABA receptorFrom Wikipedia, the free encyclopedia
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The GABA receptors are a class ofreceptors that respond to theneurotransmittergamma-aminobutyric acid (GABA), the chief inhibitory neurotransmitter in the vertebratecentral nervoussystem. There are two classes of GABA receptors: GABAAand GABAB.

GABAA receptors are ligand-gated ion channels (also known as ionotropic receptors), whereasGABAB receptors are G protein-coupled receptors (also known asmetabotropic receptors).

Contents

1 Ligand-gated ion channels: GABAAo 1.1 GABAA- subclass (formerlyGABAC)

2 G protein coupled receptor: GABAB 3 Summary 4 References

5 External links

Ligand-gated ion channels: GABAAMain article: GABAA receptor

It has long been recognized that the fast response ofneurons to GABA that is blockedbybicuculline andpicrotoxinis due to direct activation of an anionchannel.[1][2][3][4][5] This channelwas subsequently termed the GABAA receptor.[6]Fast-responding GABA receptors are membersof family ofCys-loopligand-gatedion channels.[7][8][9] Members of this superfamily, whichincludesnicotinic acetylcholine receptors, GABAA receptors, glycine and5-HT3 receptors,possess a characteristic loop formed by a disulfide bondbetween two cysteineresidues.

In ionotropic GABAA receptors, binding of GABA molecules to their binding sites in theextracellular part of receptor triggers opening of achloride ion-selective pore. The increasedchloride conductancedrives themembrane potential towards the reversal potential of the Cl ionwhich is about 65mV in neurons, inhibiting the firing of new action potentials.

However, there are numerous reports of excitatory GABAA receptors. This phenomenon is due toincreased intracellular concentration of Cl ions either during development of the nervoussystem[10][11] or in certain cell populations.[12][13][14]

After this period of development, a Chloride pump is upregulated and inserted into the cellmembrane, pumping Cl- ions into the extracellular space of the cell. Further openings via GABAbinding to the receptor then produce inhibitory responses. Over-excitation of this receptor inducesreceptor remodeling and the eventual invagination of the GABA receptor. As a result, further

GABA binding becomes inhibited and IPSPs are no longer relevant.

GABAA- subclass (formerly GABAC)

Main article: GABAA-rho receptor

A subclass ofionotropic GABA receptors, insensitive to typical allosteric modulators ofGABAA receptor channels such asbenzodiazepinesandbarbiturates,[15][16][17] was designated
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GABA receptor.[18][19] Native responses of the GABAC receptor type occur inretinalbipolar orhorizontal cells across vertebrate species.[20][21][22][23]

GABA receptors are exclusively composed of (rho) subunits that are related toGABAA receptor subunits.[24][25][26] Although the term "GABA receptor" is frequently used,GABA may be viewed as a variant within the GABAA receptor family.[7] Others have argued that

the differences between GABA and GABAA receptors are large enough to justify maintaining thedistinction between these two subclasses of GABA receptors.[27][28] However sinceGABA receptors are closely related in sequence, structure, and function to GABAA receptors andsince other GABAA receptors besides those containing subunits appear to exhibitGABA pharmacology, the Nomenclature Committee of the IUPHAR has recommend that theGABA term no longer be used and these receptors should be designated as the subfamily ofthe GABAA receptors (GABAA-).[29]

G protein coupled receptor: GABABMain article: GABAB receptor

A slow response to GABA is mediated by GABAB receptors,[30] originally defined on the basis ofpharmacological properties.[31]

In studies focused on the control of neurotransmitter release, it was noted that a GABA receptorwas responsible for modulating evoked release in a variety of isolated tissue preparations. Thisability of GABA to inhibit neurotransmitter release from these preparations was not blocked bybicuculline, was not mimicked by isoguvacine, and was not dependent on Cl, all of which arecharacteristic of theGABAAreceptor. The most striking discovery was the finding that baclofen (-parachlorophenyl GABA), a clinically employed spasmolytic[32] [33] mimicked, inastereoselective manner, the effect of GABA.

Later ligand-binding studies provided direct evidence of binding sites for baclofen on central

neuronal membranes.[34]

cDNA cloning confirmed that the GABAB receptor belongs to the familyofG-protein coupled receptors.[35]Additional information on GABAB receptors has been reviewedelsewhere.[36][37][38][39][40][41][42][43]

Summary

Thus, GABAA receptors are ligand-gated ion channels, whereas GABAB receptors are G protein-coupled receptors.

This has a parallel to several other receptors in the body, in which a single molecule binds toreceptors which function in completely different ways:

acetylcholine binds tonicotinic and muscarinic acetylcholine receptors serotonin binds to 5-HT3andmetabotropicreceptors glutamate binds toionotropic and metabotropic receptors purines bind to ionotropic nucleotide-gated P2X and G protein-coupled P2Y receptors

The NMDA receptor(NMDAR), aglutamatereceptor, is the predominant molecular device for

controllingsynaptic plasticityandmemory function.[2]
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The NMDAR is a specific type ofionotropicglutamate 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 tocations. 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 forlearning and memory. The NMDA receptor is distinct in two ways: First, it is

both ligand-gatedand voltage-dependent; second, it requires co-activation by two ligands

- glutamate andglycine[citation needed].

Contents

[hide]

1 Structure

2 Variants

o 2.1 NR1

o 2.2 NR2

o 2.3 NR2B to NR2C switch

3 Ligands

o 3.1 Agonists

o 3.2 Antagonists

o 3.3 Modulators

4 Functional role

5 Clinical significance

6 See also

7 External links

8 References

[edit]StructureThe NMDA receptor forms a heterotetramerbetween two NR1 and two NR2 subunits; two

obligatory NR1 subunits and two regionally localized NR2 subunits. A relatedgene family of NR3

A and B subunits have an inhibitory effect on receptor activity. Multiple receptorisoforms with

distinct brain distributions and functional properties arise by selective splicing of the NR1

transcripts and differential expression of the NR2 subunits.
http://en.wikipedia.org/wiki/Ionotropichttp://en.wikipedia.org/wiki/Glutamate_receptorhttp://en.wikipedia.org/wiki/Glutamate_receptorhttp://en.wikipedia.org/wiki/NMDAhttp://en.wikipedia.org/wiki/NMDAhttp://en.wikipedia.org/wiki/Selective_agonisthttp://en.wikipedia.org/wiki/Ion_channelhttp://en.wikipedia.org/wiki/Ionhttp://en.wikipedia.org/wiki/Ionhttp://en.wikipedia.org/wiki/Ionhttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid10049997-2http://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid11775847-3http://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid11399431-4http://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid17088105-5http://en.wikipedia.org/wiki/Synaptic_plasticityhttp://en.wikipedia.org/wiki/Learninghttp://en.wikipedia.org/wiki/Learninghttp://en.wikipedia.org/wiki/Memoryhttp://en.wikipedia.org/wiki/Memoryhttp://en.wikipedia.org/wiki/Ligand-gated_ion_channelhttp://en.wikipedia.org/wiki/Ligand-gated_ion_channelhttp://en.wikipedia.org/wiki/Glutamatehttp://en.wikipedia.org/wiki/Glycinehttp://en.wikipedia.org/wiki/Glycinehttp://en.wikipedia.org/wiki/Wikipedia:Citation_neededhttp://en.wikipedia.org/wiki/Wikipedia:Citation_neededhttp://en.wikipedia.org/wiki/NMDA_receptorhttp://en.wikipedia.org/wiki/NMDA_receptor#Structurehttp://en.wikipedia.org/wiki/NMDA_receptor#Variantshttp://en.wikipedia.org/wiki/NMDA_receptor#NR1http://en.wikipedia.org/wiki/NMDA_receptor#NR2http://en.wikipedia.org/wiki/NMDA_receptor#NR2B_to_NR2C_switchhttp://en.wikipedia.org/wiki/NMDA_receptor#Ligandshttp://en.wikipedia.org/wiki/NMDA_receptor#Agonistshttp://en.wikipedia.org/wiki/NMDA_receptor#Antagonistshttp://en.wikipedia.org/wiki/NMDA_receptor#Modulatorshttp://en.wikipedia.org/wiki/NMDA_receptor#Functional_rolehttp://en.wikipedia.org/wiki/NMDA_receptor#Clinical_significancehttp://en.wikipedia.org/wiki/NMDA_receptor#See_alsohttp://en.wikipedia.org/wiki/NMDA_receptor#External_linkshttp://en.wikipedia.org/wiki/NMDA_receptor#Referenceshttp://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=1http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=1http://en.wikipedia.org/w/index.php?title=Heterotetramer&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=Heterotetramer&action=edit&redlink=1http://en.wikipedia.org/wiki/Genehttp://en.wikipedia.org/wiki/Genehttp://en.wikipedia.org/wiki/Isoformhttp://en.wikipedia.org/wiki/Ionotropichttp://en.wikipedia.org/wiki/Glutamate_receptorhttp://en.wikipedia.org/wiki/NMDAhttp://en.wikipedia.org/wiki/Selective_agonisthttp://en.wikipedia.org/wiki/Ion_channelhttp://en.wikipedia.org/wiki/Ionhttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid10049997-2http://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid11775847-3http://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid11399431-4http://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid17088105-5http://en.wikipedia.org/wiki/Synaptic_plasticityhttp://en.wikipedia.org/wiki/Learninghttp://en.wikipedia.org/wiki/Memoryhttp://en.wikipedia.org/wiki/Ligand-gated_ion_channelhttp://en.wikipedia.org/wiki/Glutamatehttp://en.wikipedia.org/wiki/Glycinehttp://en.wikipedia.org/wiki/Wikipedia:Citation_neededhttp://en.wikipedia.org/wiki/NMDA_receptorhttp://en.wikipedia.org/wiki/NMDA_receptor#Structurehttp://en.wikipedia.org/wiki/NMDA_receptor#Variantshttp://en.wikipedia.org/wiki/NMDA_receptor#NR1http://en.wikipedia.org/wiki/NMDA_receptor#NR2http://en.wikipedia.org/wiki/NMDA_receptor#NR2B_to_NR2C_switchhttp://en.wikipedia.org/wiki/NMDA_receptor#Ligandshttp://en.wikipedia.org/wiki/NMDA_receptor#Agonistshttp://en.wikipedia.org/wiki/NMDA_receptor#Antagonistshttp://en.wikipedia.org/wiki/NMDA_receptor#Modulatorshttp://en.wikipedia.org/wiki/NMDA_receptor#Functional_rolehttp://en.wikipedia.org/wiki/NMDA_receptor#Clinical_significancehttp://en.wikipedia.org/wiki/NMDA_receptor#See_alsohttp://en.wikipedia.org/wiki/NMDA_receptor#External_linkshttp://en.wikipedia.org/wiki/NMDA_receptor#Referenceshttp://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=1http://en.wikipedia.org/w/index.php?title=Heterotetramer&action=edit&redlink=1http://en.wikipedia.org/wiki/Genehttp://en.wikipedia.org/wiki/Isoform


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

functional unit:

The extracellulardomain contains two globular structures: a modulatory domain and

aligand-binding domain. NR1 subunits bind the co-agonist glycine and NR2 subunits bind theneurotransmitter 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 ofpotassium

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 ofprotein kinasesand 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 byx-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.

[edit]Variants

[edit]NR1

There are eight variants of the NR1subunit produced by alternative splicing ofGRIN1:[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;

[edit]NR2
http://en.wikipedia.org/wiki/Extracellularhttp://en.wikipedia.org/wiki/Domain_(biology)http://en.wikipedia.org/wiki/Ligandhttp://en.wikipedia.org/wiki/Ligandhttp://en.wikipedia.org/wiki/Potassium_channelshttp://en.wikipedia.org/wiki/Potassium_channelshttp://en.wikipedia.org/wiki/Porehttp://en.wikipedia.org/wiki/Conductancehttp://en.wikipedia.org/wiki/Protein_kinaseshttp://en.wikipedia.org/wiki/Protein_kinaseshttp://en.wikipedia.org/wiki/Protein_phosphataseshttp://en.wikipedia.org/wiki/Protein_phosphataseshttp://en.wikipedia.org/wiki/X-ray_crystallographyhttp://en.wikipedia.org/wiki/X-ray_crystallographyhttp://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=2http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=2http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=3http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=3http://en.wikipedia.org/wiki/GRIN1http://en.wikipedia.org/wiki/GRIN1http://www.genenames.org/data/hgnc_data.php?match=GRIN1http://www.genenames.org/data/hgnc_data.php?match=GRIN1http://en.wikipedia.org/wiki/NMDA_receptor#cite_note-Stephenson_2006-6http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=4http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=4http://en.wikipedia.org/wiki/Extracellularhttp://en.wikipedia.org/wiki/Domain_(biology)http://en.wikipedia.org/wiki/Ligandhttp://en.wikipedia.org/wiki/Potassium_channelshttp://en.wikipedia.org/wiki/Potassium_channelshttp://en.wikipedia.org/wiki/Porehttp://en.wikipedia.org/wiki/Conductancehttp://en.wikipedia.org/wiki/Protein_kinaseshttp://en.wikipedia.org/wiki/Protein_phosphataseshttp://en.wikipedia.org/wiki/X-ray_crystallographyhttp://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=2http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=3http://en.wikipedia.org/wiki/GRIN1http://www.genenames.org/data/hgnc_data.php?match=GRIN1http://en.wikipedia.org/wiki/NMDA_receptor#cite_note-Stephenson_2006-6http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=4


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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 theneurotransmitterglutamate. Unlike NR1 subunits, NR2 subunits are expresseddifferentially 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 inhibitorifenprodil.

Whereas NR2Bis 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 reelinmay play a role in the NMDA

receptor maturation by increasing the NR2B subunit mobility.[11]

[edit]NR2B to NR2C switch

Granule cell precursors (GCPs) of the cerebellum, after undergoing symmetric cell division[12] in

the external granule-cell layer (EGL), migrate into the internal granule-cell layer (IGL) where they
http://en.wikipedia.org/wiki/GRIN2Ahttp://en.wikipedia.org/wiki/GRIN2Bhttp://en.wikipedia.org/wiki/GRIN2Chttp://en.wikipedia.org/wiki/GRIN2Chttp://en.wikipedia.org/wiki/GRIN2Chttp://en.wikipedia.org/wiki/GRIN2Dhttp://en.wikipedia.org/wiki/Neurotransmitterhttp://en.wikipedia.org/wiki/Neurotransmitterhttp://en.wikipedia.org/wiki/Neurotransmitterhttp://en.wikipedia.org/wiki/Glutamatehttp://en.wikipedia.org/wiki/Ifenprodilhttp://en.wikipedia.org/wiki/GRIN2Bhttp://en.wikipedia.org/wiki/GRIN2Bhttp://en.wikipedia.org/wiki/NR2Ahttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid15470155-7http://en.wikipedia.org/wiki/Excitotoxicityhttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid17360906-8http://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid17360906-8http://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid16540573-9http://en.wikipedia.org/wiki/Lethalityhttp://en.wikipedia.org/wiki/Reelinhttp://en.wikipedia.org/wiki/Reelinhttp://en.wikipedia.org/wiki/GRIN2Bhttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid17881522-10http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=5http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=5http://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid18322077-11http://en.wikipedia.org/wiki/File:Model_of_NR2_Subunit_of_NMDA_receptor_(vertebrate_and_invertebrate).jpghttp://en.wikipedia.org/wiki/File:Model_of_NR2_Subunit_of_NMDA_receptor_(vertebrate_and_invertebrate).jpghttp://en.wikipedia.org/wiki/GRIN2Ahttp://en.wikipedia.org/wiki/GRIN2Bhttp://en.wikipedia.org/wiki/GRIN2Chttp://en.wikipedia.org/wiki/GRIN2Dhttp://en.wikipedia.org/wiki/Neurotransmitterhttp://en.wikipedia.org/wiki/Glutamatehttp://en.wikipedia.org/wiki/Ifenprodilhttp://en.wikipedia.org/wiki/GRIN2Bhttp://en.wikipedia.org/wiki/NR2Ahttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid15470155-7http://en.wikipedia.org/wiki/Excitotoxicityhttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid17360906-8http://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid16540573-9http://en.wikipedia.org/wiki/Lethalityhttp://en.wikipedia.org/wiki/Reelinhttp://en.wikipedia.org/wiki/GRIN2Bhttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid17881522-10http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=5http://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid18322077-11


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downregulate NR2B and activate NR2C, a process that is independent of neuregulin beta

signaling through ErbB2 and ErbB4 receptors.[13]

[edit]Ligands

[edit]AgonistsActivation of NMDA receptors requires binding ofglutamate oraspartate (aspartate does not

stimulate the receptors as strongly).[14] In addition, NMDARs also require the binding of theco-

agonistglycinefor 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.[15] 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 glial cells, indicating a

role for glia-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 andlearning, and it has been suggested that this channel is a

biochemical substrate ofHebbian learning, where it can act as a coincidence detector for

membrane depolarization and synaptic transmission.

[edit]Antagonists

Main article: NMDA receptor antagonist

Antagonists of the NMDA receptor are used asanesthetics for animals and sometimes humans,

and are often used asrecreational drugs due to theirhallucinogenicproperties, in addition to their

unique effects at elevated dosages such asdissociation. When NMDA receptor antagonists are

given to rodents in large doses, they can cause a form ofbrain damagecalled Olney's Lesions.

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.[16]

Common NMDA receptor antagonists include:

Amantadine[17]

Ketamine

Phencyclidine (PCP)

Nitrous oxide
http://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid19244516-12http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=6http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=6http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=7http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=7http://en.wikipedia.org/wiki/Glutamic_acidhttp://en.wikipedia.org/wiki/Aspartic_acidhttp://en.wikipedia.org/wiki/Aspartic_acidhttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid15703381-13http://en.wikipedia.org/wiki/Agonisthttp://en.wikipedia.org/wiki/Agonisthttp://en.wikipedia.org/wiki/Agonisthttp://en.wikipedia.org/wiki/Glycinehttp://en.wikipedia.org/wiki/Glycinehttp://en.wikipedia.org/wiki/D-serinehttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid17033043-14http://en.wikipedia.org/wiki/Serine_racemasehttp://en.wikipedia.org/wiki/Transmembrane_potentialhttp://en.wikipedia.org/wiki/Transmembrane_potentialhttp://en.wikipedia.org/wiki/Mg_ion_(physiology)http://en.wikipedia.org/wiki/Mg_ion_(physiology)http://en.wikipedia.org/wiki/Mg_ion_(physiology)http://en.wikipedia.org/wiki/Memoryhttp://en.wikipedia.org/wiki/Learninghttp://en.wikipedia.org/wiki/Learninghttp://en.wikipedia.org/wiki/Hebbian_learninghttp://en.wikipedia.org/wiki/Hebbian_learninghttp://en.wikipedia.org/wiki/Hebbian_learninghttp://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=8http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=8http://en.wikipedia.org/wiki/NMDA_receptor_antagonisthttp://en.wikipedia.org/wiki/Anestheticshttp://en.wikipedia.org/wiki/Anestheticshttp://en.wikipedia.org/wiki/Recreational_drughttp://en.wikipedia.org/wiki/Recreational_drughttp://en.wikipedia.org/wiki/Hallucinogenichttp://en.wikipedia.org/wiki/Hallucinogenichttp://en.wikipedia.org/wiki/Dissociationhttp://en.wikipedia.org/wiki/Dissociationhttp://en.wikipedia.org/wiki/Brain_damagehttp://en.wikipedia.org/wiki/Olney's_Lesionshttp://en.wikipedia.org/wiki/Olney's_Lesionshttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-urlErowid_DXM_Vaults-15http://en.wikipedia.org/wiki/Amantadinehttp://en.wikipedia.org/wiki/Amantadinehttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-urlEffects_of_N-Methyl-D-Aspartate_.28NMDA.29-Receptor_Antagonism_on_Hyperalgesia.2C_Opioid_Use.2C_and_Pain_After_Radical_Prostatectomy_-_Full_Text_View_-_ClinicalTrials.gov-16http://en.wikipedia.org/wiki/Amantadinehttp://en.wikipedia.org/wiki/Ketaminehttp://en.wikipedia.org/wiki/Phencyclidinehttp://en.wikipedia.org/wiki/Nitrous_oxidehttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid19244516-12http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=6http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=7http://en.wikipedia.org/wiki/Glutamic_acidhttp://en.wikipedia.org/wiki/Aspartic_acidhttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid15703381-13http://en.wikipedia.org/wiki/Agonisthttp://en.wikipedia.org/wiki/Agonisthttp://en.wikipedia.org/wiki/Glycinehttp://en.wikipedia.org/wiki/D-serinehttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid17033043-14http://en.wikipedia.org/wiki/Serine_racemasehttp://en.wikipedia.org/wiki/Transmembrane_potentialhttp://en.wikipedia.org/wiki/Transmembrane_potentialhttp://en.wikipedia.org/wiki/Mg_ion_(physiology)http://en.wikipedia.org/wiki/Memoryhttp://en.wikipedia.org/wiki/Learninghttp://en.wikipedia.org/wiki/Hebbian_learninghttp://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=8http://en.wikipedia.org/wiki/NMDA_receptor_antagonisthttp://en.wikipedia.org/wiki/Anestheticshttp://en.wikipedia.org/wiki/Recreational_drughttp://en.wikipedia.org/wiki/Hallucinogenichttp://en.wikipedia.org/wiki/Dissociationhttp://en.wikipedia.org/wiki/Brain_damagehttp://en.wikipedia.org/wiki/Olney's_Lesionshttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-urlErowid_DXM_Vaults-15http://en.wikipedia.org/wiki/Amantadinehttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-urlEffects_of_N-Methyl-D-Aspartate_.28NMDA.29-Receptor_Antagonism_on_Hyperalgesia.2C_Opioid_Use.2C_and_Pain_After_Radical_Prostatectomy_-_Full_Text_View_-_ClinicalTrials.gov-16http://en.wikipedia.org/wiki/Ketaminehttp://en.wikipedia.org/wiki/Phencyclidinehttp://en.wikipedia.org/wiki/Nitrous_oxide


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Dextromethorphan and dextrorphan

Memantine

Ethanol

Riluzole (used in ALS)[18]

Xenon

HU-211 (also a cannabinoid)

Lead (Pb2+)[19]

Dual opioids and NMDA-Antagonists:

Ketobemidone

Methadone

Dextropropoxyphene Tramadol

Kratom alkaloids

Ibogaine

[edit]Modulators

The NMDA receptor is modulated by a number ofendogenous and exogenous compounds:[20]

Mg2+ not only blocksthe 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.[21]

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.

Pb2+ lead is a potent NMDAR antagonist. Presynaptic deficits resulting from Pb2+

exposure during synaptogenesis are mediated by disruption of NMDAR-dependent BDNF

signaling.

It has been demonstrated thatpolyaminesdo not directly activate NMDA receptors, but

instead act to potentiate or inhibit glutamate-mediated responses.
http://en.wikipedia.org/wiki/Dextromethorphanhttp://en.wikipedia.org/wiki/Dextrorphanhttp://en.wikipedia.org/wiki/Memantinehttp://en.wikipedia.org/wiki/Ethanolhttp://en.wikipedia.org/wiki/Ethanolhttp://en.wikipedia.org/wiki/Riluzolehttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-17http://en.wikipedia.org/wiki/Xenonhttp://en.wikipedia.org/wiki/HU-211http://en.wikipedia.org/wiki/Cannabinoidhttp://en.wikipedia.org/wiki/Leadhttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-18http://en.wikipedia.org/wiki/Ketobemidonehttp://en.wikipedia.org/wiki/Methadonehttp://en.wikipedia.org/wiki/Dextropropoxyphenehttp://en.wikipedia.org/wiki/Tramadolhttp://en.wikipedia.org/wiki/Tramadolhttp://en.wikipedia.org/wiki/Kratomhttp://en.wikipedia.org/wiki/Ibogainehttp://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=9http://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=9http://en.wikipedia.org/wiki/Endogenoushttp://en.wikipedia.org/wiki/Endogenoushttp://en.wikipedia.org/wiki/Exogenoushttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid15670959-19http://en.wikipedia.org/wiki/Mg_ion_(physiology)http://en.wikipedia.org/wiki/Mg_ion_(physiology)http://en.wikipedia.org/wiki/Mg_ion_(physiology)http://en.wikipedia.org/wiki/Channel_blockhttp://en.wikipedia.org/wiki/Channel_blockhttp://en.wikipedia.org/wiki/Membrane_potentialhttp://en.wikipedia.org/wiki/Membrane_potentialhttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid16542786-20http://en.wikipedia.org/wiki/Sodiumhttp://en.wikipedia.org/wiki/Sodiumhttp://en.wikipedia.org/wiki/Sodiumhttp://en.wikipedia.org/wiki/Sodiumhttp://en.wikipedia.org/wiki/K_ion_(physiology)http://en.wikipedia.org/wiki/K_ion_(physiology)http://en.wikipedia.org/wiki/K_ion_(physiology)http://en.wikipedia.org/wiki/Ca_ion_(physiology)http://en.wikipedia.org/wiki/Ca_ion_(physiology)http://en.wikipedia.org/wiki/Ca_ion_(physiology)http://en.wikipedia.org/wiki/Zinc#Biological_rolehttp://en.wikipedia.org/wiki/Zinc#Biological_rolehttp://en.wikipedia.org/wiki/Zinc#Biological_rolehttp://en.wikipedia.org/w/index.php?title=Pb2%2B&action=edit&redlink=1http://en.wikipedia.org/wiki/Polyaminehttp://en.wikipedia.org/wiki/Polyaminehttp://en.wikipedia.org/wiki/Polyaminehttp://en.wikipedia.org/wiki/Dextromethorphanhttp://en.wikipedia.org/wiki/Dextrorphanhttp://en.wikipedia.org/wiki/Memantinehttp://en.wikipedia.org/wiki/Ethanolhttp://en.wikipedia.org/wiki/Riluzolehttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-17http://en.wikipedia.org/wiki/Xenonhttp://en.wikipedia.org/wiki/HU-211http://en.wikipedia.org/wiki/Cannabinoidhttp://en.wikipedia.org/wiki/Leadhttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-18http://en.wikipedia.org/wiki/Ketobemidonehttp://en.wikipedia.org/wiki/Methadonehttp://en.wikipedia.org/wiki/Dextropropoxyphenehttp://en.wikipedia.org/wiki/Tramadolhttp://en.wikipedia.org/wiki/Kratomhttp://en.wikipedia.org/wiki/Ibogainehttp://en.wikipedia.org/w/index.php?title=NMDA_receptor&action=edit&section=9http://en.wikipedia.org/wiki/Endogenoushttp://en.wikipedia.org/wiki/Exogenoushttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid15670959-19http://en.wikipedia.org/wiki/Mg_ion_(physiology)http://en.wikipedia.org/wiki/Channel_blockhttp://en.wikipedia.org/wiki/Membrane_potentialhttp://en.wikipedia.org/wiki/NMDA_receptor#cite_note-pmid16542786-20http://en.wikipedia.org/wiki/Sodiumhttp://en.wikipedia.org/wiki/K_ion_(physiology)http://en.wikipedia.org/wiki/Ca_ion_(physiology)http://en.wikipedia.org/wiki/Zinc#Biological_rolehttp://en.wikipedia.org/w/index.php?title=Pb2%2B&action=edit&redlink=1http://en.wikipedia.org/wiki/Polyamine


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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

inH+ concentration, and partially inhibited by the ambient concentration of H+ underphysiological conditions.[citation needed] 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.[22]

Src kinase enhances NMDA receptor currents.[23]

Reelin modulates NMDA function through Src family kinasesandDAB1.[24] significantly

enhancing LTPin thehippocampus.

CDK5 regulates the amount ofNR2B-containing NMDA receptors on the synaptic

membrane, thus affectingsynaptic plasticity.[25][26]

[edit]Functional role

The NMDA receptor is a non-specific cation channel which can allow Ca2+, Na+, and K+ to pass

into the cell. The excitatory postsynaptic potential (EPSP) produced by activation of an NMDA

receptor increases the concentration of Ca2+ in the cell. The Ca2+ can in turn function as a second

messengerin various signaling pathways. However, the NMDA receptor cation channel is

blocked by Mg2+ at physiological levels. To unblock the channel, the postsynaptic cell must be

depolarized.[27]

The NMDA receptor therefore functions as a "molecularcoincidence detector". Its ion channel

only opens when the following two conditions are met simultaneously: glutamate is bound to the

receptor, and the postsynaptic cell is depolarized (which removes the Mg2+ blocking the channel).

This property of the NMDA receptor explains many aspects oflong term potentiation (LTP)

andsynaptic plasticity.[28]
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NMDA receptors are modulated by a number of endogenous and exogenous compounds and

play a key role in a wide range ofphysiological(e.g. memory) andpathological processes

(e.g. excitotoxicity).

[edit]Clinical significance

Recently, NMDARs were associated with a rareautoimmunedisease, 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.[29]

AMPA receptorFrom Wikipedia, the free encyclopedia

AMPA

Glutamic acid

The -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(also known as AMPA

receptor, AMPAR, orquisqualate receptor) is a non-NMDA-type ionotropictransmembrane

receptorforglutamate that mediates fastsynaptic transmission in the central nervous system(CNS).

Its name is derived from its ability to be activated by the artificial glutamate analogAMPA. The

receptor was discovered by Tage Honore and colleagues at the School of Pharmacy in Copenhagen,

and published in 1982 in the Journal of Neurochemistry.[1]AMPARs are found in many parts of
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the brain and are the most commonly found receptor in thenervous system. Of note the AMPA

receptor GluA2 (GluR2) tetramer was the 1st and currently only glutamate receptor ion channel to be

crystallized.

Contents

[hide]

1 Structure and Function

o 1.1 Subunit Composition

o 1.2 Ion Channel Function

2 Synaptic Plasticity

3 Ligands

o 3.1 Agonists

o 3.2 Positive allosteric modulators

o 3.3 Antagonists

o 3.4 Negative allosteric modulators

4 See also

5 References

6 External links

[edit]Structure and Function

[edit]Subunit Composition

AMPARs are composed of four types of subunits, designated

as GluR1 (GRIA1),GluR2(GRIA2), GluR3 (GRIA3), andGluR4, alternatively called GluRA-D2

(GRIA4), which combine to form tetramers.[2][3][4] Most AMPARs are heterotetrameric, consisting of

symmetric 'dimer of dimers' of GluR2 and either GluR1, GluR3 or GluR4.[5][6]Dimerization starts in

the Endoplasmic reticulumwith the interaction of n-terminal LIVBP domains, then "zips up" through the

ligand-binding domain into the transmembrane ion pore.[6]

The conformation of the subunit protein in the plasma membrane caused controversy for some time.

While the amino acid sequence of the subunit indicated that there were four transmembrane domains

(parts of the protein that pass through the plasma membrane), proteins interacting with the subunit

indicated that the N-terminuswas extracellular while the C-terminus was intracellular. If each of the

four transmembrane domains went all the waythrough the plasma membrane, then the two termini

would have to be on the same side of the membrane. Eventually, it was discovered that the second

transmembrane domain is not in facttransat all, but kinks back on itself within the membrane and
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ligand binding domain

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