TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
*1.A.10.1.1









AMPA-selective glutamate ionotropic channel receptor (GIC; AMPAR), kainate-subtype, GluR-K1; GluR1; GluR-A; GluA1; Gria1 of 906 aas (preferentially monovalent cation selective). Contributes to amygdala-dependent emotional learning and fear conditioning (Humeau et al., 2007). Transmembrane AMPAR regulatory protein (TARP) gamma-7 (TC#8.A.16.2.5) selectively enhances the synaptic expression of Ca2+-permeable (CP-AMPARs) and suppresses calcium-impermeable (CI-AMPAR) activities (Studniarczyk et al. 2013).  Thus, TARPs modulate the pharmacology and gating of AMPA-type glutamate receptors (Soto et al. 2014).  TARPs interact with the N-terminal domain of the AMPAR and control channel gating; residues in the receptor and the TARP involved in this interaction have been identified (Cais et al. 2014).  The auxilary protein, Shisa9 or CKAMP44 (UniProt acc# B4DS77), has a C-terminal PDZ domain that allows interaction with scaffolding proteins and AMPA glutamate receptors (Karataeva et al. 2014).  The transmembrane domain alone can tetramerize (Gan et al. 2016). The most potent and well-tolerated AMPA receptor inhibitors, used to treat epilepsy, act via a noncompetitive mechanism.  The crystal structures of the rat AMPA-subtype GluA2 receptor in complex with three noncompetitive inhibitors have been solved. The inhibitors bind to a binding site, completely conserved between rat and human, at the interface between the ion channel and linkers connecting it to the ligand-binding domains (Yelshanskaya et al. 2016). The endogenous neuropeptide, cyclopropylglycine, at a physiological concentration of 1 μM, enhances the transmembrane AMPA currents in rat cerebellar Purkinje cells (Gudasheva et al. 2016). The energetics of glutamate binding have been estimated (Yu and Lau 2017).

Eukaryota
Metazoa
GluR-K1 of Rattus norvegicus
*1.A.10.1.2









GIC, AMPA-subtype, GluR4 or GluR-D (preferentially monovalent cation selective)
Eukaryota
Metazoa
GluR-D of Rattus norvegicus
*1.A.10.1.3









GIC, NMDA-subtype, Grin C2 (highly permeable to Ca2+ and monovalent cations). A single residue in the GluN2 subunit controls NMDA receptor channel properties via intersubunit interactions (Retchless et al., 2012). Memantine (Namenda) is prescribed as a treatment for moderate to severe Alzheimer's Disease. Memantine functions by blocking the NMDA receptor, and the sites of interaction have been identified (Limapichat et al. 2013).  Genetic mutations in multiple NMDAR subunits cause various childhood epilepsy syndromes (Li et al. 2016). NMDA receptor gating is complex, exhibiting multiple closed, open, and desensitized states, but the structure-energy landscape of gating for the rat homologue has been mapped (Dolino et al. 2017).

Eukaryota
Metazoa
NMDA receptor, Grin C2, of Homo sapiens
*1.A.10.1.4









AMPA glutamate receptor 3 (GluR3) (non-selective monovalent cation channel and Ca2+  channel) (Ayalon et al., 2005; Midgett et al., 2012). Regulated by AMPA receptor regulatory proteins (TARPs) including stargazin and CNIH auxiliary subunits (Kim et al., 2010; Straub and Tomita, 2011; Jackson and Nicoll, 2011; Bats et al., 2012; Rigby et al. 2015). The domain architecture of a calcium-permeable AMPA receptor in a ligand-free conformation has been solved (Midgett et al., 2012). The TARP, stargazin, is elevated in the somatosensory cortex of Genetic Absence Epilepsy Rats (Kennard et al. 2011). TARPs alter the conformation of pore-forming subunits and thereby affect antagonist interactions (Cokić and Stein 2008).  The structural basis of AMPAR regulation by TARP gamma2, or stargazin (STZ) involves variable interaction stoichiometries of the AMPAR-TARP complex, with one or two TARP molecules binding one tetrameric AMPAR (Twomey et al. 2016).  The ion channel extracellular collar plays a role in gating and represents a hub for powerful allosteric modulation of AMPA receptor function (Yelshanskaya et al. 2017). The A653T mutation stabilizes the closed configuration of the channel and affects duration of sleep and awake periods in both humans and mice (Davies et al. 2017).

Eukaryota
Metazoa
GluR3 of Homo sapiens (P42263)
*1.A.10.1.5









The homomeric cation channel/glutamate receptor/kainate 1, GluR5 (weakly responsive to glutamate) (expressed in the developing nervous system) (Bettler et al., 1990).  The 3-d structures of the protein have been determined with agonists and antagonists.  The agonist, domoic acid, stabilizes the ligand-binding core of the iGluR5 complex in a conformation that is 11 degrees more open than the conformation observed when the full agonist, (S)-glutamate, is bound (Hald et al. 2007). Kainate receptors regulate KCC2 expression in the hippocampus (Pressey et al. 2017).

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Eukaryota
Metazoa
GluR5 of Rattus norvegicus
(P22756)
*1.A.10.1.6









The heteromeric monovalent cation/Ca2+ channel/glutamate (NMDA) receptor NMDAR1/NMDAR2A/NMDAR2B/NMDAR2C) (Monyer et al., 1992). Note: NR2B is the same as NR3, GluN2A, GRIN2A or subunit epsilon (Schüler et al., 2008). Mediates voltage- and Mg2+-dependent control of Na+ and Ca2+ permeability (Yang et al., 2010).  Mutations in the subunit, GRIN1, a 1464 aa protein, identified in patients with early-onset epileptic encephalopathy and profound developmental delay, are located in the transmembrane domain and the linker region between the ligand-binding and transmembrane domains (Yuan et al. 2014; Ohba et al. 2015).  Karakas and Furukawa 2014 determined the crystal structure of the heterotetrameric GluN1-GluN2B NMDA receptor ion channel at 4 Å resolution. The receptor is arranged as a dimer of GluN1-GluN2B heterodimers with the twofold symmetry axis running through the entire molecule composed of an amino terminal domain, a ligand-binding domain, and a transmembrane domain.  The GluN2 subunit regulates synaptic trafficking of AMPA in the neonatal mouse brain (Hamada et al. 2014).  GRIN1 and GRIN2A mutations are associated with severe intellectual disability with cortical visual impairment, epilepsy and oculomotor and movement disorders being discriminating phenotypic features (Lemke et al. 2016; Chen et al. 2017).The cryoEM structure of a triheteromeric receptor including GluN1 (glycine binding), GluN2A and GluN2B (both glutamate binding)has been solved with and without a GluN2B the allosteric antagonist, Ro 25-6981 (et al. 2017). Ogden et al. 2017 implicated the pre-M1 region in gating, provided insight into how different subunits contribute to gating, and suggested that mutations in the pre-M1 helix, such as those that cause epilepsy and developmental delays, can compromise neuronal health.

Eukaryota
Metazoa
NR1/NR2A or NR2B or NR2C of Rattus norvegicus
NR1 (Q05586)
NR2A (O08948)
NR2B (Q00960)
NR2C (Q62644)
*1.A.10.1.7









The glutamate receptor 1.1 precursor (Ligand-gated channel 1.1, AtGLR1 (Kang and Turano, 2003))
Eukaryota
Viridiplantae
GLR1 of Arabidopsis thaliana (Q9M8W7)
*1.A.10.1.8









The mouse glutamate receptor δ-2 subunit precursor (GluR δ-2, GluR delta subunit, or GluD2) (Uemura et al., 2004).  The 3-d structure in the synaptic junctional complex with presynaptic β-neurexin 1 (β-NRX1 or NRXN1A; Q9ULB1 = the human homologue) and the C1q-like synaptic organizer, cerebellin-1 (Cbln1; 193 aas, 1 or 2 TMSs; Q9R171 = the human homolgue) has been solved (Elegheert et al. 2016).

Eukaryota
Metazoa
GluR δ2 of Mus musculus (Q61625)
*1.A.10.1.9









The ionotropic glutamate receptor kainate 4 precursor (Glutamate receptor, KA-1 or EAA1) (Kamboj et al., 1994)
Eukaryota
Metazoa
KA1 of Homo sapiens (Q16099)
*1.A.10.1.10









The homo- and heteromeric glutamate receptor, GLR3.3/3.4 (Desensitized in 3 patterns: (1) by Glu alone; (2) by Ala, Cys, Glu or Gly; (3) by Ala, Cys, Glu, Gly, Ser or Asn (Stephens et al., 2008).

Eukaryota
Viridiplantae
GLR3.3/GLR3.4 receptor of Arabidopsis thaliana
GLR3.3 (Q9C8E7)
GLR3.4 (Q8GXJ4)
*1.A.10.1.11









GriK2; GluK2; GluR6 glutamate receptor, ionotropic kainate 2. The 3-d structure is known (2XXY_A). The domain organization and function have been analyzed by Das et al. (2010).  Two auxiliary subunits, Neto1 and Neto2 (Neuropilin and tolloid-like proteins) alter the trafficking, channel kinetics and pharmacology of the receptors (Howe 2014).  They reduce inward rectification without altering calcium permeability (Fisher and Mott 2012). Interactions between the pore helix (M2) and adjacent segments of the transmembrane inner (M3) and outer (M1) helices may be involved in gating (Lopez et al. 2013). Mutations in the human GRIK2 (GLUR6) cause moderate-to-severe nonsyndromic autosomal recessive mental retardation (Motazacker et al. 2007). Kainate receptors regulate KCC2 (TC# 1.A.10.1.11) expression in the hippocampus (Pressey et al. 2017). GluR6, carrying the pore loop plus adjacent transmembrane domains of the prokaryotic, glutamate-gated, K+-selective GluR0 (TC# 1.A.10.2.1), adopted several electrophysiological properties of the donor pore uponpore transplantation (Hoffmann et al. 2006).

Eukaryota
Metazoa
Grik2 of Rattus norvegicus (P42260)
*1.A.10.1.12









The NMDA receptor. The crystal structure of the N-terminal domains (GluN1 and GluN2) have been determined (PDB#3QEL; Talukder and Wollmuth, 2011). The ligand-specific deactivation time courses of GluN1/GluN2D NMDA receptors have been measured (Vance et al., 2011).  NMDA receptors are Hebbian-like coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltage-dependent magnesium block to open an ion conductive pore. Lee et al. 2014 presented X-ray structures of the Xenopus laevis GluN1-GluN2B NMDA receptor with the allosteric inhibitor, Ro25-6981, partial agonists and the ion channel blocker, MK-801. Receptor subunits are arranged in a 1-2-1-2 fashion, demonstrating extensive interactions between the amino-terminal and ligand-binding domains. The 3-TMS transmembrane domains harbour a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a approximately twofold symmetric arrangement of ion channel pore loops.

Eukaryota
Metazoa
NMDA receptor of Xenopus laevis (Q91977)
*1.A.10.1.13









Glu2 AMPA receptor (GluR-2; GluA2).  The 3-d structure is known at 3.6 Å resolution.  It shows a 4-fold axis of symmetry in the transmembrane domain, and a 2-fold axis of symmetry overall, although it is a homotetramer (Sobolevsky et al. 2009). A structure showing an agoniar-bound form of the rat GluA2 receptor revealed conformational changes that occur during gating (Yelshanskaya et al. 2014). GluR2 interacts directly with β3 integrin (Pozo et al., 2012).  In general, integrin receptors form macromolelcular complexes with ion channels (Becchetti et al. 2010).  TARPS are required for AMP receptor function and trafficking, but seven other auxiliary subunits have also been identified (Sumioka 2013). For example, AMPA receptors are regulated by S-SCAM through TARPs (Danielson et al. 2012).  The C-terminal domains of various TARPs (TC#8.A.16.2) play direct roles in the regulation of GluRs (Sager et al. 2011).  Whole-genome analyses have linked multiple TARP loci to childhood epilepsy, schizophrenia and bipolar disorders (Kato et al. 2010). Thus, TARPs emerge as vital components of excitatory synapses that participate both in signal transduction and in neuropsychiatric disorders. The architecture of a fully occupied GluR2-TARP complex has been illucidated by cryoEM, showing the homomeric GluA2 AMPA receptor saturated with TARP Υ2 subunits, showing how the TARPs are arranged with four-fold symmetry around the ion channel domain, making extensive interactions with the M1, M2 and M4 TMSs (Zhao et al. 2016).

Eukaryota
Metazoa
GluR-2 of Homo sapiens (P42262)
*1.A.10.1.14









Ionotropic receptor 25a, Ir25a.  Not involved in salt sensing (Zhang et al. 2013).  It resets the circadian clock in response to temperature (Chen et al. 2015).

Eukaryota
Metazoa
Ir25a of Drosophila melanogaster
*1.A.10.1.15









Glutamate ionotropic receptor homologue

Eukaryota
Metazoa
Glutamate receptor in Daphnia pulex (water flea)
*1.A.10.1.16









Olfactory ionotropic receptor, Ir93a of 842 aas

Eukaryota
Metazoa
Ir93a of Panulirus argus (spiny lobster)
*1.A.10.1.17









Ionotropic sodium channel; attractive, sodium gustatory sensory receptor for positive salt taste.  Not involved in salt avoidance which uses a distinct receptor (Zhang et al. 2013). 

Eukaryota
Metazoa
Ir76b of Drosophila melanogaster
*1.A.10.1.18









Calcium channel of 551 aas, Glr1 (Wheeler and Brownlee 2008).

Glr1 of Chlamydomonas reinhardtii
*1.A.10.1.19









Olfactory glutamate-like ionotropic receptor, kainate 2 isoform X1 of 754 aas and 4 TMSs. Chen et al. 2017 identify 102 putative IR genes, (dubbed AalbIr genes) in the mosquito Aedes albopictus (Skuse), 19 of which showed expression in the female antenna. These putative olfactory AalbIRs share four conservative hydrophobic domains similar to the transmembrane and ion channel pore regions found in conventional iGluRs. To determine their potential functions in host-seeking, Chen et al. 2017 compared their transcript expression levels in the antennae of blood-fed females with that of non-blood-fed females. Three AalbIr genes showed downregulation when the mosquito finished a bloodmeal.

Eukaryota
Metazoa
Olfactory receptor of Aedes albopictus (Asian tiger mosquito) (Stegomyia albopicta)
*1.A.10.1.20









Heteromeric ionotropic NMDA receptor (NMDAR) consisting of two subunits, GluN1 (938 aas) and GluN2A (1464 aas).  Positions of the Mg2+ and Ca2+ ions in the ion channel divalent cation binding site have been proposed, and differences in the structural and dynamic behavior of the channel proteins in the presence of Mg2+ or Ca2+ have been analyzed (Mesbahi-Vasey et al. 2017).

Eukaryota
Metazoa
NMDAR of Homo sapiens
*1.A.10.1.21









Glutamate receptor 1, GluR1; Glr-1 of 962 aas and 5 TMSs.  Plays a role in controlling movement in response to environmental cues such as food availability and mechanosensory stimulation such as the nose touch response (Campbell et al. 2016). Regluated by SOL1 (TC# 8.A.47.2.1) (Walker et al. 2006).

Eukaryota
Metazoa
Glr-1 of Caenorhabditis elegans
*1.A.10.1.22









NMDA-like glutamate receptor, NR1, of 964 aas and 4 TMSs.  It functions in the organization of feeding, locomotory and defensive behaviors. Two are present, NR1-1 and NR1-2 in nurrons (Ha et al. 2006).

Eukaryota
Metazoa
NR1 of Aplysia californica (California sea hare)
*1.A.10.2.1









Glutamate-gated ionotropic K+ channel receptor, GluR0 (5TMSs). X-ray structures are available (PDB: 1IIT) (Lee et al. 2005; Lee et al. 2008)  GluR6 (TC# 1.A.10.1.11), carrying the pore loop plus adjacent transmembrane domains of this prokaryotic, glutamate-gated, K+-selective GluR0, adopted several electrophysiological properties of the donor pore upon pore transplantation (Hoffmann et al. 2006).

Bacteria
Cyanobacteria
GluR0 of Synechocystis sp. PCC6803
*1.A.10.2.2









Probable Ionotropic glutamate receptor (GluR)

Bacteria
Bacteroidetes/Chlorobi group
GluR homologue of Algoriphagus sp. PR1 (A3I049)
*1.A.10.2.3









Probably Ionotropic glutamate receptor (GluR) 

Bacteria
Bacteroidetes/Chlorobi group
GluR homologue of Chlorobium luteolum (Q3B5G3)
*1.A.10.2.4









Probable Ionotropic glutamate receptor (GluR)

Bacteria
Proteobacteria
GluR homologue of Vibrio fischeri (B5FDH7)
*1.A.10.2.5









Uncharacterized protein of 1003 aas and 5 - 7 TMSs

Eukaryota
Viridiplantae
UP of Chlamydomonas reinhardtii (Chlamydomonas smithii)