Gria2 (rat GluA2, UniProt P19491) - manual literature synthesis

No deep-research API was available for this review; this file is a manual synthesis
built from the cached publications in publications/ and the UniProt record
(Gria2-uniprot.txt). Every claim carries its source.

Identity and architecture

• GluA2 (GluR2, GluR-B) is the AMPA-type ionotropic glutamate receptor subunit 2;
  UniProt: "Ionotropic glutamate receptor that functions as a ligand-gated cation channel,
  gated by L-glutamate and glutamatergic agonists such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
  acid (AMPA), quisqualic acid, and kainic acid" [file:rat/Gria2/Gria2-uniprot.txt CC FUNCTION].
• Member of the glutamate-gated ion channel family (TC 1.A.10.1); PANTHER PTHR18966;
  domains: amino-terminal domain (ANF receptor, PF01094), ligand-binding S1/S2 (PF10613),
  pore/transmembrane region (PF00060) [file:rat/Gria2/Gria2-uniprot.txt DR lines].
• Topology: extracellular N-terminus (22-543), M1, re-entrant pore loop M2 (592-607),
  M3, extracellular S2 loop, M4, cytoplasmic C-tail (834-883) [UniProt FT].
• Crystal structure of homotetrameric rat GluA2 PMID:19946266.
  The receptor is a dimer of dimers with symmetry mismatch between extracellular and pore layers.
• In heteromeric GluA1/2-TARP gamma8 receptors "the core subunits arrange to give the GluA2
  subunit dominant control of gating" PMID:30872532.
• ATD (NTD) drives subfamily-specific and heteromeric assembly: "AMPA receptor GluR1- and
  GluR2-ATDs form tightly associated dimers" PMID:19461580; "Heteromerization is dominant,
  occurs at the level of the dimer, and results in a preferential incorporation of the
  functionally critical GluA2 subunit" PMID:21317873.

Channel function and the Q/R site

• Q/R site in M2 controls Ca2+ permeability PMID:1653450.
• RNA editing (Q607R): "Heteromerically expressed edited GLUR2 (R) receptor complexes are
  impermeable to calcium, whereas the unedited (Q) forms are highly permeable to divalent cations"
  [UniProt RNA EDITING, PMID:1653450]. So native (edited) GluA2 renders AMPARs Ca2+-impermeable;
  Ca2+-permeable AMPA channel activity is a property of GluA2-lacking receptors or of the
  unedited/mutant GluA2 constructs used experimentally (GluR-B(Q), GluR-B(N)) PMID:11773314.
• Flip/flop splicing tunes desensitization; edited homomeric GluA2(R) gives almost no current,
  so kinetics were measured on unedited GluR2Q PMID:10704491.
• Kainate is a weak partial agonist of GluA2 (structural impediment to lobe closure)
  [PMID:21846932 full text]; GluA2 is not a kainate-selective receptor.
• Auxiliary subunits: TARPs (gamma-2, gamma-5, gamma-7, gamma-8) [PMID:18817736, PMID:19234459,
  PMID:21172611, PMID:30872532] and cornichons CNIH2/3 PMID:19265014.

Trafficking via the C-terminal tail

• PDZ ligand (-SVKI) binds class II PDZ proteins GRIP1/ABP/GRIP2 and PICK1
  [PMID:9069286, PMID:9768844 "ABP binds to the GluR2/3 C-terminal VKI-COOH motif via class II
  hydrophobic PDZ interactions", PMID:10027300, PMID:10340301].
• Ser880 phosphorylation by PKC decreases GRIP1 binding but not PICK1 binding and promotes
  internalization PMID:11007883; occurs during cerebellar LTD PMID:10856222.
• Tyr876 phosphorylation strengthens GRIP1 binding and gates homeostatic upscaling
  PMID:32071234; GRIP1-GluA2 interaction needed for LTP-related
  insertion PMID:32948689 and scaling up PMID:26109571.
• NSF binds residues Lys844-Gln853 (Asn851 critical); NSF-binding peptide reduces AMPAR EPSCs
  PMID:9697854; GluR2-NSF-SNAP complex is ATP-hydrolysis reversible PMID:9697855;
  NSF/SNAPs disassemble GluR2-PICK1 PMID:11931741; Plk2 displaces NSF and promotes GluA2 loss
  PMID:20802490.
• AP-2 mu2 binds a basic motif in the tail and drives clathrin-dependent endocytosis
  PMID:17289840; Syt3 binds GluA2 and drives activity-dependent endocytosis PMID:30545844.
• GluA2-3Y peptide (blocks regulated endocytosis) blocks LTD in NAc and VTA and LTD-dependent
  behaviours [PMID:16311338, PMID:21187978, PMID:37190555].
• PICK1 restricts GluA2 from synapses after OGD, producing Ca2+-permeable GluA2-lacking AMPARs
  and delayed cell death [PMID:19321442, full text: surface biotinylation shows "a time-dependent
  reduction in GluR2 surface expression by OGD"]; glycine chemLTP produces a transient
  PICK1-dependent switch PMID:22915106.

Localization

• Postsynaptic density of asymmetric synapses, dendrites and dendritic spines; essentially absent
  presynaptically in hippocampus PMID:10701825; spines of thalamo-amygdaloid synapses with a
  large cytoplasmic pool PMID:17207780.
• Presynaptic pools in some circuits: axonal growth cones and synaptic vesicle membranes
  PMID:12554656, corticostriatal/thalamostriatal terminals PMID:15610164, GABAergic terminals
  in dorsal horn PMID:15844209, presynaptic active zone and small vesicles of Schaffer
  collaterals PMID:28057533, presynaptic synaptosome fraction PMID:16903873.

Disease/pathology context (non-core)

• Abeta oligomers (ADDLs) bind preferentially to GluA2-containing complexes PMID:20032460.
• GluA2 down-regulation by tributyltin increases glutamate vulnerability PMID:19591855.