Glutamate receptor (GluA2)

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 arranged in a 'Y'-shape with the ^[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.

• The 'top' layer is composed of the

This .

• participates directly in agonist/competitive antagonist binding, affects activation gating, and is the portion that forms the 'middle' layer.

in the structure.

The small molecule ^[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].

• is the portion that forms the membrane-spanning on the 'bottom' of the solved structure.

To help give a better idea of how the glutamate receptor is oriented on the cell surface in the membrane 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 :
      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 -

• .
• And the .
• While that is going on, in the ATD there is also inter-pair interactions mediated between . Note this view really highlights the two-fold symmetry between the A-B and C-D pairs at the level of the ATD.

In the LBD domain -

• Whereas in the ATD domain A and B paired up, in the LBD.
• And the .
• While that is going on, in the LBD there is also extensive inter-pair interactions mediated between . Note this view highlights the two-fold symmetry between the A-D and B-C pairs at the level of the LBD. .

The domain swapping can be observed from the side following the backbone of each chain as well: , , , and . And .

• As explored further in a later section below , the . Thus, remarkably, the symmetry switches from an overall two-fold symmetry for the ATD and LBD to four-fold for the TMD.

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

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.

• Subunit A is equivalent to Subunit C (in the small structure window in this section). In the main window, a .
• Subunit B is equivalent to Subunit D (in the small structure window in this section). In the main window, a .

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:

• .
• .
• .

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

• The segments shown again, .

There is consistent with the channel being in a closed state with the antagonist (ZK200775) bound to the LBD.

It is that occludes the channel. [BE PATIENT as a small surface is generated.]

Note . 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.

• To better observe the contributions of each of the membrane segments to the subunit-subunit interactions, . [Note: this scene generates a substantial surface which may take about a minute to calculate. Be patient.]

Note that the M4 segment associates with the ion-channel core of an adjacent subunit.

.

• 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^[10][11][12]. Here the pore region of Streptomyces lividans potassium channel (1bl8), specifically the . The of the K+ channel even though these portions weren't even included in the calculation of the alignment seen here.

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

• 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

• 1iiw and 1iit and 1ii5 – Prokaryotic glutamte receptor (Glur0) Apo structure and with various ligands bound, including glutmate ^[13]. This helped cement the notion the glutamate and potassium receptors share structural similarity and possibly evolutionary ancestry ^[10][11].
• 1bl8 and 1jq1 and 1jq2 – Streptomyces lividans KcsA potassium channel^[12][14]: The M1, M2 and M3 segments of GluA2's ion channel overlap remarkably well with the structurally equivalent portions KcsA.
• Molecular Playground/Glutamate Receptor
• Ligand Binding N-Terminal of Metabotropic Glutamate Receptors

• Receptor
• Transmembrane (cell surface) receptors
• Ionotropic receptors

References

Additional Literature and Resources

• For additional information, see: Alzheimer's Disease
• For additional information, see: Membrane Channels & Pumps
• Glutamate Receptor on the cover of Nature
• Glutamate receptor Wikipedia entry
• Glutamate Receptors page at the MRC Centre for Synaptic Plasticity at the University of Bristol

Page started with original page seeded by OCA on Wed Dec 16 11:24:54 2009 for 3kg2.