Glutamate receptor (GluA2)

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The 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 [1][2][3][4]. Groundbreaking work elucidated the structure of a complete functional, homomeric glutamate receptor[5][6] and that structure, 3kg2, is the subject of this page.


Structure of the Glutamate Receptor (GluA2)

Overview

The homomeric rat GluA2 receptor has four subunits arranged in a 'Y'-shape with the 'top' being about three times the width of the 'bottom'[5]. This structure is a functional homotetramer of the AMPA-subtype; native ionotropic glutamate receptors are almost exclusively heterotetramers. .

Domains

The subunits themselves are modular [7]and the major domains are found in layers in the tetrameric structure.

This extracellular domain is glycosylated.
  • The ligand-binding domain (LBD) participates directly in agonist/competitive antagonist binding, affects activation gating, and is the portion that forms the 'middle' layer.
The competitive antagonist ZK200775 is bound to the LBD in the structure.
The small molecule ZK200775, a phosphonate quinoxalinedione AMPA antagonist[8], 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[9].
To help give a better idea of how the glutamate receptor is oriented on the cell surface in the membrane lipid bilayer, a slab representative of hydrophobic core of the lipid bilayer as calculated by the 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.
 
  • 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.

Domain swapping between the subunits and symmetry mismatch between the domains

  • Unanticipated is the domain swapping and crossover that occurs between the subunits interactions. In order to discuss the remarkable swapping, it is best to designate each subunit with a letter:
        A       B       C        D
  • Considering each chain, there is crossover as the pairs of subunits seen in the ATD are swapped in the LBD.
In the ATD domain -
In the LBD domain -
The domain swapping can be observed from the side following the backbone of each chain as well: A chain, B chain, C chain, and D chain. And all for comparison.

The rat glycosylated glutamate receptor in complex with a competitive antagonist (3kg2)

Drag the structure with the mouse to rotate


Subunit Non-Equivalence, Transmembrane Domain Architecture and the Occluded Pore

Glutamate Receptor Structure (PDB code 3kg2)

Drag the structure with the mouse to rotate

A is equivalent to C

Drag the structure with the mouse to rotate

B is equivalent to D

Drag the structure with the mouse to rotate

Subunit non-equivalence

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 below and the morphs referred to below will show in the main window on the left:

However, each of the subunit A/C group though is distinct from those of the B/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 Subunit A' and Subunit B.
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 Subunit A and Subunit B:

Subunit A morphing into Subunit B best illustrates how portions, especially the linkers, of the protein change between the two conformational forms.

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.

Transmembrane domain architecture and the occluded pore

  • M1
  • M2
  • M3
  • M4
There is no pore visible in the center consistent with the channel being in a closed state with the antagonist (ZK200775) bound to the LBD.
It is the tight helix crossing of specifically the M3 helices that occludes the channel. [BE PATIENT as a small surface is generated.]
Note the differences between the conformations of the carboxy-termini ('top') of the subunit A/C and B/D M3 segments. 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.
Note that the M4 segment associates with the ion-channel core of an adjacent subunit.

Details of Structure Featured

3kg2 is a 4 chains structure of sequences from Rattus norvegicus. Full crystallographic information is available from 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.

Reference for the structure

  1. Sobolevsky AI, Rosconi MP, Gouaux E. X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature. 2009 Dec 10;462(7274):745-56. Epub . PMID:19946266 doi:10.1038/nature08624

3D structures of glutamate receptors

Ionotropic Glutamate Receptors

See Also

References

  1. ↑ Jin R, Singh SK, Gu S, Furukawa H, Sobolevsky AI, Zhou J, Jin Y, Gouaux E. Crystal structure and association behaviour of the GluR2 amino-terminal domain. EMBO J. 2009 Jun 17;28(12):1812-23. Epub 2009 May 21. PMID:19461580 doi:10.1038/emboj.2009.140
  2. ↑ Kumar J, Schuck P, Jin R, Mayer ML. The N-terminal domain of GluR6-subtype glutamate receptor ion channels. Nat Struct Mol Biol. 2009 Jun;16(6):631-8. Epub 2009 May 24. PMID:19465914 doi:10.1038/nsmb.1613
  3. ↑ Karakas E, Simorowski N, Furukawa H. Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit. EMBO J. 2009 Dec 16;28(24):3910-20. Epub . PMID:19910922 doi:10.1038/emboj.2009.338
  4. ↑ Armstrong N, Sun Y, Chen GQ, Gouaux E. Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature. 1998 Oct 29;395(6705):913-7. PMID:9804426 doi:10.1038/27692
  5. ↑ 5.0 5.1 Sobolevsky AI, Rosconi MP, Gouaux E. X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature. 2009 Dec 10;462(7274):745-56. Epub . PMID:19946266 doi:10.1038/nature08624
  6. ↑ Wollmuth LP, Traynelis SF. Neuroscience: Excitatory view of a receptor. Nature. 2009 Dec 10;462(7274):729-31. PMID:20010675 doi:10.1038/462729a
  7. ↑ Wo ZG, Oswald RE. Unraveling the modular design of glutamate-gated ion channels. Trends Neurosci. 1995 Apr;18(4):161-8. PMID:7539962
  8. ↑ Turski L, Huth A, Sheardown M, McDonald F, Neuhaus R, Schneider HH, Dirnagl U, Wiegand F, Jacobsen P, Ottow E. ZK200775: a phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10960-5. PMID:9724812
  9. ↑ Walters MR, Kaste M, Lees KR, Diener HC, Hommel M, De Keyser J, Steiner H, Versavel M. The AMPA antagonist ZK 200775 in patients with acute ischaemic stroke: a double-blind, multicentre, placebo-controlled safety and tolerability study. Cerebrovasc Dis. 2005;20(5):304-9. Epub 2005 Aug 30. PMID:16131799 doi:10.1159/000087929
  10. ↑ 10.0 10.1 Wo ZG, Oswald RE. Unraveling the modular design of glutamate-gated ion channels. Trends Neurosci. 1995 Apr;18(4):161-8. PMID:7539962
  11. ↑ 11.0 11.1 Wood MW, VanDongen HM, VanDongen AM. Structural conservation of ion conduction pathways in K channels and glutamate receptors. Proc Natl Acad Sci U S A. 1995 May 23;92(11):4882-6. PMID:7761417
  12. ↑ 12.0 12.1 Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science. 1998 Apr 3;280(5360):69-77. PMID:9525859
  13. ↑ Chen GQ, Cui C, Mayer ML, Gouaux E. Functional characterization of a potassium-selective prokaryotic glutamate receptor. Nature. 1999 Dec 16;402(6763):817-21. PMID:10617203 doi:10.1038/45568
  14. ↑ Liu YS, Sompornpisut P, Perozo E. Structure of the KcsA channel intracellular gate in the open state. Nat Struct Biol. 2001 Oct;8(10):883-7. PMID:11573095 doi:10.1038/nsb1001-883

Additional Literature and Resources

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