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| [[Image:3KG2-snapshot-900x900-14724.jpg|left|270px]]
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| The [http://en.wikipedia.org/wiki/Glutamate_receptor glutamate receptor]is the ion channel opened by glutamate that keeps neurons in touch by mediating fast cell-to-cell information transfer in the nervous system. Several studies have revealed structures for portions of the glutamate receptor <ref name="r80">PMID: 19461580</ref><ref name="r14">PMID: 19465914</ref><ref name="r22">PMID: 19910922</ref><ref>PMID: 9804426</ref>. Groundbreaking work elucidated the structure of a complete functional, homomeric glutamate receptor<ref name="main">PMID:19946266</ref><ref>PMID: 20010675</ref> and that structure, [[3kg2]], is the subject of this page.
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| ==Structure of the Glutamate Receptor (GluA2)==
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| <StructureSection load='1dq8' size='500' side='right' scene='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Default3kg2/1' caption='Sglutamate receptor ([[3kg2]])'>
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| The homomeric rat GluA2 receptor <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Default3kg2/1'>has four subunits</scene> arranged in a 'Y'-shape with the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Meas3kg2/1'>'top' being about three times the width of the 'bottom'</scene><ref name="main" />. This structure is a functional homotetramer of the AMPA-subtype; native ionotropic glutamate receptors are almost exclusively heterotetramers. {{Link Toggle FancyCartoonHighQualityView}}.
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| ===Domains===
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| The subunits themselves are modular <ref>PMID: 7539962</ref>and the major domains are found in layers in the tetrameric structure.
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| <!-- select all; spacefill off; select hetero; color cpk; wireframe 0.35; spacefill 0.4; select zk1; spacefill on; color cpk; -->
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| *The 'top' layer is composed of the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atd_domain/4'>amino-terminal domain(ATD)</scene>
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| ::This <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atd_gly/2'>extracellular domain is glycosylated</scene>.
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| *<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Lbd_domain/4'>The ligand-binding domain (LBD)</scene> participates directly in agonist/competitive antagonist binding, affects activation gating, and is the portion that forms the 'middle' layer.
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| ::<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Lbd_zk1/2'>The competitive antagonist ZK200775 is bound to the LBD</scene> in the structure.
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| ::The small molecule <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Zk1_zoom/1'>ZK200775, a phosphonate quinoxalinedione AMPA antagonist</scene><ref>PMID: 9724812</ref>, was studied as a treatment for stroke because it had demonstrated neuroprotective efficacy in experimental models of stroke and tolerability in healthy volunteers; however, in a multicenter, double-blind, randomized, placebo-controlled phase II trial, it was found to have significant sedative effects in patients with acute stroke which precludes its further development as a neuroprotective agent<ref>PMID: 16131799</ref>.
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| *<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Tmd_domain/2'>The transmembrane domain (TMD)</scene> is the portion that forms the membrane-spanning on the 'bottom' of the solved structure.
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| ::To help give a better idea of how the glutamate receptor is oriented on the cell surface in the membrane lipid bilayer, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/3kg2opm_mem/11'>a slab representative of hydrophobic core of the lipid bilayer</scene> as calculated by the [http://opm.phar.umich.edu/protein.php?pdbid=3kg2 Orientations of Proteins in Membranes database] (University of Michigan, USA) is shown with the red patch of spheres indicating the boundary of the hydrophobic core closet to the outside of the cell and the dark blue patch of spheres indicating the boundary closest to the inside of the cell.
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| ::[[Image:Opm_periplasmic_topology.gif]]
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| * The carboxy-terminal domain that plays a role in both receptor localization and regulation is not seen in the structure but would be below the transmembrane domain as it is cytoplasmic.
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| ===Domain swapping between the subunits and symmetry mismatch between the domains===
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| *Unanticipated is the domain swapping and crossover that occurs between the subunits interactions. In order to discuss the remarkable swapping, it is best to <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Default3kg2letter/4'>designate each subunit with a letter</scene>: <br> '''<span style="color:forestgreen">A</span>''' '''<span style="color:red">B</span>''' '''<span style="color:cornflowerblue">C</span>''' '''<!--<span style="color:#FFFF80">D</span>-->D'''
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| *Considering each chain, there is crossover as the pairs of subunits seen in the ATD are swapped in the LBD.
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| ::In the ATD domain -
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| ::*<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Ab_in_atd/1'>Portions of the A and B subunits pair up</scene>.
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| ::*And the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Cd_in_atd/2'>Portions of the C and D subunits form a pair</scene>.
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| ::*While that is going on, in the ATD there is also inter-pair interactions mediated between <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Abcd_in_atd/2'>subunits B and D</scene>. Note this view really highlights the two-fold symmetry between the A-B and C-D pairs at the level of the ATD.
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| ::In the LBD domain -
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| ::*Whereas in the ATD domain A and B paired up, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Ad_in_lbd/3'>portions of the A and D subunits pair up</scene> in the LBD.
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| ::*And the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Bc_in_lbd/1'>Portions of the B and C subunits form a pair</scene>.
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| ::*While that is going on, in the LBD there is also extensive inter-pair interactions mediated between <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Abcd_in_lbd/6'>subunits A and C</scene>. Note this view highlights the two-fold symmetry between the A-D and B-C pairs at the level of the LBD. <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Abcd_in_lbdside/1'>Looking from the side helps in seeing the inter-pair interactions between A and C</scene>.
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| :The domain swapping can be observed from the side following the backbone of each chain as well: <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Swap_full_side/1'>A chain</scene>, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Swap_full_side/2'>B chain</scene>, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Swap_full_side/3'>C chain</scene>, and <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Swap_full_side/5'>D chain</scene>. And <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Default3kg2letter/4'>all for comparison</scene>.
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| *As explored further in [[#Transmembrane domain architecture and the occluded pore|a later section below]] , the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Tmd_domain_4fold/2'>symmetry is an overall four-fold for the TMD</scene>. Thus, remarkably, the symmetry switches from an overall two-fold symmetry for the ATD and LBD to four-fold for the TMD.
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| </StructureSection>
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| ===Subunit non-equivalence===
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| <StructureSection load='1dq8' size='500' side='right' scene ='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Default3kg2/1' caption='Glutamate Receptor Structure>
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| <table width='240' align='left' cellpadding='2'><tr><td bgcolor='#eeeeee'><applet load='3kg2' size='240' frame='true' align='left' scene='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Ac3kg2letter/1' caption='A is equivalent to C'/></td><td bgcolor='#eeeeee'><applet load='3kg2' size='240' frame='true' align='left' scene='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Bd3kg2letter/2' caption='B is equivalent to D'/></td></tr></table>
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| As a result of the swapping and symmetry mismatch, there is subunit non-equivalence; even though all the chains are the same chemically, there are two distinct conformations of the subunits. This means there are two matching pairs of subunits. The pairs are illustrated on the left and the morphs referred to below will show on the right:
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| * <span style="color:forestgreen">Subunit '''A</span>''' is equivalent to <span style="color:cornflowerblue">Subunit '''C'''</span> (ABOVE). On the right, a <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atocmorph/5'>morph showing the equivalency of the two subunits by rotating around the axis of their symmetry</scene>.
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| * <span style="color:red">Subunit '''B</span>''' is equivalent to Subunit '''D''' (ABOVE). <!--<span style="color:#FFFF80">Subunit '''D'''</span>(<--says 'Subunit D' in hard-to-read gold color matching the structure)--> On the right, a <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Btodmorph/5'>morph showing the equivalency of the two subunits by rotating around the axis of their symmetry</scene>.
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| However, each of the subunit '''<span style="color:forestgreen">A</span>'''/<span style="color:cornflowerblue">'''C'''</span> group though is distinct from those of the <span style="color:red">'''B</span>'''/'''D''' group. Having established the two equivalent groups we can simplify the discussion of the relationship between the two pairs by focusing solely on comparing <span style="color:forestgreen">Subunit '''A'</span>''' and <span style="color:red">Subunit '''B</span>'''.<br>
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| The domains themselves stay relatively static between the two conformational forms, with the linkers in between and the resulting arrangement changing. This is best illustrated by superposition of the individual domains of <span style="color:forestgreen">Subunit '''A</span>''' and <span style="color:red">Subunit '''B</span>''':
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| *<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atdatobsuper/4'>Superposition of the ATD</scene>.
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| *<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Lbdatobsuper/2'>Superposition of the LBD</scene>.
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| *<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Tmdatobsuper/1'>Superposition of the TMD</scene>.
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| <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Atobmorph/2'>Subunit A morphing into Subunit B best illustrates how portions, especially the linkers, of the protein change</scene> between the two conformational forms.<br>
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| {{Button Toggle AnimationOnPause}}
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| :The linkers are key; besides playing roles in domain swapping and resolving the symmetry mismatch, they are also responsible for relaying the modulation signals from the ATD to the other domains and signaling the conformational change of the LBD to control the opening and closing of the pore. Beyond the two conformations seen here though this particular structure ([[3kg2]]) of the receptor does not shed light on the transduction process.
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| ===Transmembrane domain architecture and the occluded pore===
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| *<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Transmemlabeled/1'>Transmembrane segments M1 to M4 depicted in different colors to show the approximate 4-fold rotational symmetry of the entire ion channel domain.</scene>
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| ::* '''<span style="color:coral">M1</span>'''
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| ::* '''<span style="color:lightgreen">M2</span>'''
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| ::* '''<span style="color:violet">M3</span>'''
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| ::* '''<span style="color:lightskyblue">M4</span>'''
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|
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| *The segments shown again, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Transmem/4'>this time parallel to the four-fold axis</scene>.
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| ::There is <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Transmemclosed/1'>no pore visible in the center</scene> consistent with the channel being in a closed state with the antagonist (ZK200775) bound to the LBD.
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| ::It is <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/M3_closed/3'>the tight helix crossing of specifically the M3 helices</scene> that occludes the channel. [BE PATIENT as a small surface is generated.]
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| ::Note <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/M3_closed_top/1'>the differences between the conformations of the carboxy-termini ('top') of the subunit A/C and B/D M3 segments</scene>. This is in part is why the symmetry is only approximately four-fold and is one of the several intriguing observations in regard to symmetry for this macromolecule. In fact, the location of two-fold symmetry at the ends of M3 is just above the portion that spans the membrane and is close to the last region of the structure that doesn't show four-fold symmetry as abruptly below this point everything is four-fold symmetric.
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| *To better observe the contributions of each of the membrane segments to the subunit-subunit interactions, <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Trans_surf/4'>the transmembrane domains of three subunits are shown in a surface representation with the segments M1-M4 of the fourth subunit shown as green cylinders</scene>. <nowiki>[</nowiki>Note: this scene generates a substantial surface which may take about a minute to calculate. Be patient.<nowiki>]</nowiki>
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| ::Note that the M4 segment associates with the ion-channel core of an adjacent subunit.
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| :{{Link Toggle FancyCartoonHighQualityView}}.
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| *The TMD domain of the GluA2 receptor shares structural and sequence similarity with the pore region of the potassium (K+), as hinted at by earlier work<ref name ="pot1">PMID: 7539962</ref><ref name ="pot2">PMID: 7761417</ref><ref name ="pot3">PMID: 9525859</ref>. Here the pore region of ''Streptomyces lividans'' potassium channel ([[1bl8]])<scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Gluvspottmd/4'> superposed with the TMD domain of GluA2</scene>, specifically the <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Gluvspottmdm3/1'>inner helix of the K+ channel aligned with the M3 segment</scene>. The <scene name='User:Wayne_Decatur/Sandbox_Glutamate_receptor/Gluvspottmdm1/2'>M1 segment of GluA2 also overlays well with the outer helix</scene> of the K+ channel even though these portions weren't even included in the calculation of the alignment seen here.
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| </StructureSection>
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| ==Details of Structure Featured==
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| [[3kg2]] is a 4 chains structure of sequences from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KG2 OCA]. Although it is billed as the first structure of a full-length glutamate receptor, the carboxy-terminal domain is not present in the structure.
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|
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| ==Reference for the structure==
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| <ref group="xtra">PMID:19946266</ref><references group="xtra"/>
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|
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| ==See Also==
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| * [[3kgc]] – GluA2 ligand-binding core complex bound with glutamate
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| * [[2a5t]] – GluN1-GluN2A ligand-binding domain heterodimer
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| * [[2a5s]] – GluN2A ligand-binding domain bound with glutamate
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| * [[3h5w]] and [[3h5v]] – Crystal structure of the GluR2 amino-terminal domain<ref name="r80" />
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| * [[1gr2]] – Structure of a glutamate-receptor ligand-binding core in complex with kainate<ref>PMID: 9804426</ref>
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| * [[3jpy]] and [[3jpw]] – Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit<ref name="r22" />
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| * [[1iiw]] and [[1iit]] and [[1ii5]] – Prokaryotic glutamte receptor (Glur0) Apo structure and with various ligands bound, including glutmate <ref>PMID: 10617203</ref>. This helped cement the notion the glutamate and potassium receptors share structural similarity and possibly evolutionary ancestry <ref name="pot1" /><ref name="pot2" />.
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| * [[3hgh]] and [[3hgh]] – The N-terminal domain of a GluR6-subtype glutamate receptor<ref name="r14" />
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| * [[1bl8]] and [[1jq1]] and [[1jq2]] – ''Streptomyces lividans'' KcsA potassium channel<ref name="pot3" /><ref>PMID:11573095</ref>: The M1, M2 and M3 segments of GluA2's ion channel overlap remarkably well with the structurally equivalent portions KcsA.
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| * [[Molecular Playground/Glutamate Receptor]]
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|
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| ==References==
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| {{Reflist}}
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|
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| ==Additional Literature and Resources==
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| * For additional information, see: [[Alzheimer's Disease]]
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| * For additional information, see: [[Membrane Channels & Pumps]]
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| * [http://www.nature.com/nature/journal/v462/n7274/covers/ Glutamate Receptor on the cover] of [http://www.nature.com/ Nature]
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| * [http://en.wikipedia.org/wiki/Glutamate_receptor Glutamate receptor Wikipedia entry]
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| * [http://www.bristol.ac.uk/synaptic/receptors/#ionotropic Glutamate Receptors page] at the [http://www.bristol.ac.uk/synaptic/ MRC Centre for Synaptic Plasticity at the University of Bristol]
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| ''Page started with original page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Dec 16 11:24:54 2009 for [[3kg2]].''
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|
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| [[Category: Rattus norvegicus]]
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| [[Category: Gouaux, E.]]
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| [[Category: Rosconi, M P.]]
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| [[Category: Sobolevsky, A I.]]
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| [[Category: Alternative splicing]]
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| [[Category: Cell membrane]]
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| [[Category: Glycoprotein]]
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| [[Category: Ion channel]]
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| [[Category: Ion transport]]
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| [[Category: Membrane]]
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| [[Category: Membrane protein]]
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| [[Category: Postsynaptic cell membrane]]
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| [[Category: Receptor]]
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| [[Category: Rna editing]]
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| [[Category: Synapse]]
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| [[Category: Tetramer]]
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| [[Category: Transmembrane]]
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| [[Category: Transport]]
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| [[Category: Neuron]]
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| [[Category: Neurotransmitter]]
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| [[Category: Potassium Channels]]
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| [[Category: RCSB PDB Molecule of the Month]]
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| [[Category: Streptomyces lividans]]
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| [[Category: Cabral, J M.]]
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| [[Category: Chait, B T.]]
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| [[Category: Cohen, S L.]]
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| [[Category: Doyle, D A.]]
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| [[Category: Gulbis, J M.]]
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| [[Category: Kuo, A.]]
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| [[Category: Mackinnon, R.]]
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| [[Category: Pfuetzner, R A.]]
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| [[Category: Integral membrane protein]]
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| [[Category: Potassium channel]]
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