| TCID | Name | Domain | Kingdom/Phylum | Protein(s) |
|---|---|---|---|---|
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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). A mature complex contains GluR1, TARPs, and PSD-95 (Fukata et al. 2005). The receptor 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). The TMEM108 protein (Q6UXF1 of 575 aas and 2 TMSs, N- and C-terminal, is required for surface expression of AMPA receptors (Jiao et al. 2017). CERC-611 is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor regulatory protein (TARP; TC# 8.A.16) gamma-8 (Witkin et al. 2017). Drug effects, regulatory protein modulators and positive allosteric modulators have been reviewed (Fu et al. 2019). Herguedas et al. 2019 presented a cryo-EM structure of the heteromeric GluA1/2 receptor associated with two transmembrane AMPAR regulatory protein (TARP) gamma8 auxiliary subunits, the principal AMPAR complex at hippocampal synapses. The native heterotetrameric AMPA-R adopts various conformations, which reflect a variable separation of the two dimeric extracellular amino-terminal domains; members of the stargazin/TARP family of transmembrane proteins co-purify with AMPA-Rs and contribute to the density representing the transmembrane region of the complex. Glutamate and cyclothiazide altered the conformational equilibrium of the channel complex, suggesting that desensitization is related to separation of the N-terminal domains (Nakagawa et al. 2005). Positive allosteric modulators (PAMs) of AMPA receptors boost cognitive performance in clinical studies, and mibampator and BIIB104 discriminate between AMPARs complexed with distinct TARPs, and particularly those with lower stargazin/gamma2 efficacy such as BIIB104 (Ishii et al. 2020). Yelshanskaya et al. 2020 identified trans-4-butylcyclohexane carboxylic acid (4-BCCA) binding sites in the transmembrane domain of AMPA receptors, at the lateral portals formed by TMSs M1-M4. At this binding site, 4-BCCA is very dynamic, assumes multiple poses and can enter the ion channel pore. Cannabidiol inhibits febrile seizure by modulating AMPA receptor kinetics through its interaction with the N-terminal domain of GluA1/GluA2 (Yu et al. 2020). Inhibition of AMPA receptors (AMPARs, e.g., TC# 1.A.10.1.1) containing transmembrane AMPAR regulatory protein gamma-8 (TC# 8.A.61.1.10) with JNJ-55511118 (TC#8.A.179.1.1) shows preclinical efficacy in reducing chronic repetitive alcohol self-administration (Hoffman et al. 2021). Mechanisms underlying TARP modulation of the GluA1/2-gamma8 AMPA receptor have been studied (Herguedas et al. 2022). L-Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS). Its associated receptors, localized on neuronal and non-neuronal cells, mediate rapid excitatory synaptic transmission in the CNS and regulate a wide range of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors selective to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) also play an important role in numerous neurological disorders. Golubeva et al. 2022 examined the structural diversity of chemotypes of agonists, competitive AMPA receptor antagonists, positive and negative allosteric modulators, TARP-dependent allosteric modulators, ion channel blockers ans their binding sites. | Eukaryota |
Metazoa, Chordata | GluR-K1 of Rattus norvegicus |
|
1.A.10.1.2 | Glutamate receptor 4, GIC, AMPA-subtype, GluR4, GRIA4 or GluR-D (preferentially monovalent cation selective). Binding of the excitatory neurotransmitter, L-glutamate, induces a conformation change, leading to the opening of the cation channel, thereby converting the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4, CACNG7 or CACNG8, GluR4 shows resensitization characterized by a delayed accumulation of current flux upon continued application of glutamate (Gill et al. 2008; Birdsey-Benson et al. 2010). De novo variants in GRIA4 lead to intellectual disability with or without seizures, gait abnormalities, problems of social behavior, and other variable features (Martin et al. 2017). | Eukaryota |
Metazoa, Chordata | 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). NMDARs are tetrameric complexes consisting of two glycine-binding GluN1 and two glutamate-binding GluN2 subunits. Four GluN2 subunits encoded by different genes can produce up to ten different di- and triheteromeric receptors. These heteromeric systems have been modeled (Gibb et al. 2018). A conserved glycine associated with diseases permits NMDA receptors to acquire high Ca2+ permeability (Amin et al. 2018). The ND2 protein (see TC# 3.D.1.6.1), a component of the NMDAR complex, enables Src tyrosine protein kinase (TC# 8.A.23.1.12) regulation of NMDA receptors (Scanlon et al. 2017). Drug effects, regulatory protein modulators and positive allosteric modulators have been reviewed (Fu et al. 2019). | Eukaryota |
Metazoa, Chordata | NMDA receptor, Grin C2, of Homo sapiens |
|
1.A.10.1.4 | AMPA glutamate receptor 3 (GluR3, GluA3. GRIA3. LLUR3. GLURC) (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). The tetramer exhibits 4 distinct conductase leves due to independent subunit activation. Perampanel is an anticonvulsant drug that regulates gating (Yuan et al. 2019). Tetramerization of the AMPA receptor glutamate-gated ion channel is regulated by auxiliary subunits (Certain et al. 2023). A synopsis of multitarget therapeutic effects of anesthetics on depression has been published (Wu and Xu 2023). | Eukaryota |
Metazoa, Chordata | GluR3 of Homo sapiens (P42263) |
|
1.A.10.1.5 | The homomeric cation channel/glutamate receptor/kainate 1, GluR5, GluK1, GRIK1 of 918 aas and (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). GluR5/ERK signaling is regulated by the phosphorylation and function of the glycine receptor alpha1ins subunit (TC# 9.A.14.3.4) in the spinal dorsal horn of mice (Zhang et al. 2019). The human ortholog is 918 aas long and 97% identical to the rat homolog. (-)-Arctigenin and a series of new analogues are AMPA and kainate receptor antagonists of human homomeric GluA1 and GluK2 receptors (Rečnik et al. 2021). | Eukaryota |
Metazoa, Chordata | 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 allosteric antagonist, Ro 25-6981 (Lü et al. 2017). Ogden et al. 2017 implicated the pre-M1 region in gating, providing insight into how different subunits contribute to gating, and suggesting that mutations in the pre-M1 helix, such as those that cause epilepsy and developmental delays, can compromise neuronal health. The severity of GRIN2A (Glu2A)-related disorders can be predicted based on the positions of the mutations in the encoding gene (Strehlow et al. 2019). Knock-in mice expressing an ethanol-resistant GluN2A NMDA receptor subunit show altered responses to ethanol (Zamudio et al. 2019). Results of McDaniel et al. 2020 revealed the role of the pre-M1 helix in channel gating, implicated the surrounding amino acid environment in this mechanism, and suggested unique subunit-specific contributions of pre-M1 helices to GluN1 and GluN2 gating. The human ortholog is 998.5% identical. An autism-associated mutation in GluN2B prevents NMDA receptor trafficking and interferes with dendrite growth (Sceniak et al. 2019). The binding of calcium-calmodulin to the C-terminus of GluN1 has long range allosteric effects on the extracellular segments of the receptor that may contribute to the calcium-dependent inactivation (Bhatia et al. 2020). GluN1 interacts with PCDH7 (O60245) to regulate dendritic spine morphology and synaptic function (Wang et al. 2020).Pluripotential GluN1 (NMDA NR1) functions in cellular nuclei in pain/nociception (McNearney and Westlund 2023). | Eukaryota |
Metazoa, Chordata | 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, Streptophyta | GLR1 of Arabidopsis thaliana (Q9M8W7) |
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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, Chordata | 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).Molecular dynamic simulations revealed that water-soluble QTY variants of glutamate transporters, EAA1, EAA2 and EAA3, retain the conformational characteristics of their native transporters (Karagöl et al. 2024). | Eukaryota |
Metazoa, Chordata | 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). A regulatory mechanism underlies Ca2+ homeostasis by sorting and activation of AtGLRs by AtCNIHs (see for example, 8.A.61.1.9) (Wudick et al. 2018). May be responsible in part for Cd2+ uptake (Chen et al. 2018). GLR3.3 and GLC3.6 (TC# 1.A.10.1.24) (but not GLR3.4) play different roles in nervous system-like signaling in plant defense by a mechanism that differs substantially from that in animals (Toyota et al. 2018). Members of the banana GLR gene family have been identified, and expression analyses in response to low temperature and abscisic acid/methyl jasmonate concentrations have been reported (Luo et al. 2023). | Eukaryota |
Viridiplantae, Streptophyta | GLR3.3/GLR3.4 receptor of Arabidopsis thaliana GLR3.3 (Q9C8E7) GLR3.4 (Q8GXJ4) |
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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 upon pore transplantation (Hoffmann et al. 2006). Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders (Stolz et al. 2021). Concanavalin A modulation of kainate receptor function is mediated by a shift in the conformation of the kainate receptor toward a tightly packed extracellular domain (Gonzalez et al. 2021). Partial agonism in heteromeric GLUK2/GLUK5 kainate receptor has been documented, and partial agonism observed with AMPA binding is mediated primarily due to differences in the GluK2 subunit, highlighting the distinct contributions of the subunits towards activation (Paudyal et al. 2023). Kainate receptors (KARs) are a subtype of ionotropic glutamate receptor (iGluR) channels, a superfamily of ligand-gated ion channels which mediate the majority of excitatory neurotransmission in the central nervous system. KARs modulate neuronal circuits and plasticity during development and are implicated in neurological disorders, including epilepsy, depression, schizophrenia, anxiety, and autism (Gangwar et al. 2024). Calcium-permeable KARs undergo ion channel block. Gangwar et al. 2024 presented closed-state structures of GluK2 KAR homotetramers in complex with ion channel blockers NpTx-8, PhTx-74, Kukoamine A, and spermine. Blockers reside inside the GluK2 ion channel pore, intracellular to the closed M3 helix bundle-crossing gate, with their hydrophobic heads filling the central cavity and positively charged polyamine tails spanning the selectivity filter. Molecular dynamics (MD) simulations of our structures illuminate interactions responsible for different affinity and binding poses of the blockers. The structures elucidate the trapping mechanism of KAR channel block and provide a template for designing new blockers that can selectively target calcium-permeable KARs in neuropathologies (Gangwar et al. 2024). | Eukaryota |
Metazoa, Chordata | Grik2 of Rattus norvegicus (P42260) |
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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. GRIN2D mediates developmental and epileptic encephalopathy (XiangWei et al. 2019). | Eukaryota |
Metazoa, Chordata | NMDA receptor of Xenopus laevis (Q91977) |
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1.A.10.1.13 | Glu2 AMPA receptor (GluR-2; GluR2-flop; CX614; 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). The binding mode and sites for prototypical negative allosteric modulators at the GluA2 AMPA receptor revealing new details of the molecular basis of molulator binding and mechanisms of action (Stenum-Berg et al. 2019). Drug effects, regulatory protein modulators and positive allosteric modulators have been reviewed (Fu et al. 2019). TARP γ2 converts the desensitized state to the high-conductance state which exhibits tighter coupling between subunits in the extracellular parts of the receptor (Carrillo et al. 2020). | Eukaryota |
Metazoa, Chordata | GluR-2 of Homo sapiens (P42262) Drug effects, regulatory protein modulators and positive allosteric modulators have been reviewed (Fu et al. 2019). |
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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, Arthropoda | Ir25a of Drosophila melanogaster |
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1.A.10.1.15 | Glutamate ionotropic receptor homologue | Eukaryota |
Metazoa, Arthropoda | Glutamate receptor in Daphnia pulex (water flea) |
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1.A.10.1.16 | Olfactory ionotropic receptor, Ir93a of 842 aas | Eukaryota |
Metazoa, Arthropoda | Ir93a of Panulirus argus (spiny lobster) |
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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, Arthropoda | Ir76b of Drosophila melanogaster |
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1.A.10.1.18 | Calcium channel of 551 aas, Glr1 (Wheeler and Brownlee 2008). | Viridiplantae, Chlorophyta | Glr1 of Chlamydomonas reinhardtii | |
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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, Arthropoda | Olfactory receptor of Aedes albopictus (Asian tiger mosquito) (Stegomyia albopicta) |
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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). GRIN variants in receptor M2 channel pore-forming loop are associated with neurological diseases (Li et al. 2019). Disease-associated variants have revealed mechanistic aspect of the NMDA receptor (Amin et al. 2021). Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors (Iacobucci et al. 2021). The gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors have been reported (Wang et al. 2021). GluN2A and GluN2B NMDA receptors apparently use distinct allosteric routes (Tian et al. 2021). A negative allosteric modulatory site in the GluN1 M4 determines the efficiency of neurosteroid modulation (Langer et al. 2021). Excitatory signaling mediated by NMDAR is critical for brain development and function, as well as for neurological diseases and disorders. Channel blockers of NMDARs can be used for treating depression, Alzheimer's disease, and epilepsy. Chou et al. 2022 monitored the binding of three clinically important channel blockers: phencyclidine, ketamine, and memantine in GluN1-2B NMDARs at local resolutions of 2.5-3.5 Å around the binding site. The channel blockers form interactions with pore-lining residues, which control mostly off-speeds but not on-speeds (Chou et al. 2022). NMDAR channel blockers include MK-801, phencyclidine, ketamine, and the Alzheimer's disease drug memantine, can bind and unbind only when the NMDAR channel is open. NMDAR channel blockers can enter the channel through two routes: the well-known hydrophilic path from extracellular solution to channel through the open channel gate, and also a hydrophobic path from plasma membrane to channel through a gated fenestration (Wilcox et al. 2022). Pregnane-based steroids are positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations (Kysilov et al. 2022). The NMDA receptor C-terminal domain signals in development, maturity, and disease (Haddow et al. 2022). Blood tissue Plasminogen Activator (tPA) of liver origin contributes to neurovascular coupling involving brain endothelial N-Methyl-D-Aspartate (NMDA) receptors (Furon et al. 2023). Two gates mediate NMDA receptor activity and are under subunit-specific regulation (Amin et al. 2023). One of the main molecular mechanisms of ketamine action is the blockage of NMDA-activated glutamate receptors (Pochwat 2022). The S1-M1 linker of the NMDA receptor controls channel opening (Xie et al. 2023). Binding and dynamics demonstrated the destabilization of ligand binding for the S688Y mutation in the NMDA receptor GluN1 subunit (Chen et al. 2023). The functional effects of disease-associated NMDA receptor variants have been reviewed (Moody et al. 2023). Co-activation of NMDAR and mGluRs controls protein nanoparticle-induced osmotic pressure in neurotoxic edema (Zheng et al. 2023). Disease-associated nonsense and frame-shift variants resulting in the truncation of the GluN2A or GluN2B C-terminal domain decreases NMDAR surface expression and reduces potentiating effects of neurosteroids (Kysilov et al. 2024). De novo GRIN variants in the M3 helix associated with neurological disorders control channel gating of the NMDA receptor (Xu et al. 2024). Ketamine is a rapid and potent antidepressant. Ketamine injection in depressive-like mice specifically blocks NMDARs in lateral habenular (LHb) neurons, but not in hippocampal pyramidal neurons (Chen et al. 2024). This regional specificity depended on the use-dependent nature of ketamine as a channel blocker, local neural activity, and the extrasynaptic reservoir pool size of NMDARs. Activating hippocampal or inactivating LHb neurons swapped their ketamine sensitivity. Conditional knockout of NMDARs in the LHb occluded ketamine's antidepressant effects and blocked the systemic ketamine-induced elevation of serotonin and brain-derived neurotrophic factor in the hippocampus (Chen et al. 2024). | Eukaryota |
Metazoa, Chordata | NMDAR of Homo sapiens |
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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, Nematoda | Glr-1 of Caenorhabditis elegans |
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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, Mollusca | NR1 of Aplysia californica (California sea hare) |
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1.A.10.1.23 | Ionotropic glutamate receptor, GluR1 (GluR-1, GluR1-flip; GRIA1; GluH1; CTZ; GluA1) of 906 aas and 4 - 6 TMSs. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter, L-glutamate, induces a conformational change, leading to the opening of the cation-specific channel, thereby converting the chemical signal to an electrical impulse upon entry of Na+ and Ca2+. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, it shows resensitization characterized by a delayed accumulation of current flux upon continued application of glutamate (Kato et al. 2010). The polyamines, spermine, spermidine and putrescine can be drawn into the permeation pathway and get stuck, blocking the movement of other ions. The degree of this polyamine-mediated channel block is highly regulated by processes that control the free cytoplasmic polyamine concentration, the membrane potential, and the iGluR subunit composition (Bowie 2018). (-)-Arctigenin and a series of new analogues have been synthesised and tested for their potential as AMPA and kainate receptor antagonists of human homomeric GluA1 and GluK2 receptors, and thus potential drugs for epilepsy treatment (Rečnik et al. 2021). It may play a role in osteoporosis (Wu et al. 2023).
| Eukaryota |
Metazoa, Chordata | GluR-1 of Homo sapiens |
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1.A.10.1.24 | Glutamate-gated receptor 3.6 of 903 aas, GLR3.6. It probably acts as non-selective cation channel, transporting Ca2+ into the cell. It mediates leaf-to-leaf wound signaling. GLR3/6 may be involved in light-signal transduction and calcium homeostasis via the regulation of calcium influx into cells (Mousavi et al. 2013). Together with GLR3.3 (TC# 1.A.10.1.10), it plays a roles in nervous system-like signaling in plant defense. GLR3.3 and GLR3.6 play different roles by a mechanism that differs substantially from that in animals (Toyota et al. 2018). The orthologous channel protein in Dionaea muscipula may play a role in touch-induced hair calcium-electrical signals that excite the Venus flytrap (Scherzer et al. 2022). | Eukaryota |
Viridiplantae, Streptophyta | GLR3.6 of Arabidopsis thaliana |
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1.A.10.1.25 | NMDA receptor subtype 1, NMDAR1, of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. This protein plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. It mediates neuronal functions in glutamate neurotransmission and is involved in cell surface targeting of NMDA receptors. It plays a role in associative learning and in long-term memory consolidation (Xia et al. 2005). F654A and K558Q mutations affect ethanol-induced behaviors in Drosophila.(Troutwine et al. 2019).
| Eukaryota |
Metazoa, Arthropoda | NMDAR of Drosophila melanogaster (Fruit fly) |
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1.A.10.1.26 | Ionotropic receptor 21a, Ir21a, of 842 aas and 5 TMSs. Ir21a is a cooling receptor that drives heat seaking in insects to their warm blooded hosts (Greppi et al. 2020). Although Ir21a mediates heat avoidance in Drosophila, it drives heat seeking and heat-stimulated blood feeding in Anopheles. At a cellular level, Ir21a is essential for the detection of cooling, suggesting that during evolution, mosquito heat seeking relied on cooling-mediated repulsion. Thus, the evolution of blood feeding in Anopheles involves repurposing an ancestral thermoreceptor from non-blood-feeding Diptera (Greppi et al. 2020). | Eukaryota |
Metazoa, Arthropoda | Ir21a of Drosophila melanogaster |
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1.A.10.1.27 | Ionotropic receptor precursor, Ir21a, of 948 aas and 5 TMSs. They are found in the sensory endings of neurons in antenna (Greppi et al. 2020). | Eukaryota |
Metazoa, Arthropoda | Ir21a of Aedes aegypti (yellow fever mosquito) |
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1.A.10.1.28 | Glutamate receptor ionotropic, kainate 5, GluK5 or GRIK5, of 980 aas and 4 TMSs. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds kainate > quisqualate > domoate > L-glutamate >> AMPA >> NMDA = 1S,3R-ACPD. The transciption profile (transcriptome) of its gene as well as those of other Ca2+ transporters has been determined as a function of embryonic stage in mice, up until birth (Bouron 2020). Partial agonism in heteromeric GLUK2/GLUK5 kainate receptor has been documented, and partial agonism observed with AMPA binding is mediated primarily due to differences in the GluK2 subunit, highlighting the distinct contributions of the subunits towards activation (Paudyal et al. 2023). | Eukaryota |
Metazoa, Chordata | GRIK5 of Homo sapiens |
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1.A.10.1.29 | Fusion protein with an N-terminal glycine receptor/chloride channel domain (residues 1 - 470) like 1.A.9.3.1 and a C-terminal glutamate receptor/cation channel domain (residues 500 to the end) like 1.A.10.1.13. This fusion protein is from Tupaia chinensis (chinese tree shrew), and the two domains are 93.8% and 97.4% identical to the two proteins (both from Homo sapiens) that they hit in TCDB as noted above. It should be noted that the fusion proteins reported here and in TC#s 1.A.10.1.20 - 23 could reflect the presence of true fusion proteins, or they could be a result of sequencing errors. | Eukaryota |
Metazoa, Chordata | Fusion protein of Tupaia chinensis |
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1.A.10.1.30 | Fusion protein having an N-terminal domain homologous to a glycine receptor (GlyR; residues 1 - 466, 66% identical to TC# 1.A.9.3.1 (GlyR of Homo sapiens)), a central domain homologous to a glutamate receptor (GluR; residues 459 - 1296, 85.5% identical to 1.A.10.1.13, GluR of Homo sapiens)), and a C-terminal domain homologous to a DMT carrier (TC# 2.A.7.8.1, an uncharacerized protein, Yrr6 of Caenorhabditis elegans). | Eukaryota |
Metazoa, Chordata | GlyR-GluR-DMT fusion protein of Bagarius yarrelli |
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1.A.10.1.31 | Fusion protein of 2281 aas and 3 TMSs, two plus a central P-loop at residues 546 - 640 followed by one more TMS (residues 806 - 825) within an N-terminal glutamate receptor domain (residues 1 - 888) similar to that of TC# 1.A.10.1.6 (61% identity) and a C-terminal protein kinase domain (residues 1670 - 2273) homologous to the entirety of TC# 8.A.104.1.4 of 671 aas; 64% identity. The central part of this large fusion protein shows sequence similarity (~40% identity) with a nuclear chromatin condensation inducer (TC#3.A.18.1.1; Q9UKV3). | Eukaryota |
Metazoa, Chordata | Fusion protein of Scophthalmus maximus |
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1.A.10.1.33 | Fusion protein of 1324 aas and 7 putative TMSs in a 1 (N-terminal) + 2 TMSs with a central P-loop + 3 TMSs + 1 C-terminal TMS. The N-terminal ionotropic glutamate receptor , kainate 2-like domain is 43% identical to TC#1.A.10.1.11 while the C-terminal domain is homologous to the N-terminal part of TC# 1.A.9.1.6 (residues 1005 to 1239 in this fusion protein. | Eukaryota |
Metazoa, Arthropoda | Fusion protein of Dermatophagoides pteronyssinus |
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1.A.10.1.34 | Glutamate receptor, ionotropic, delta-1, GRID1or GluD1, of 1009 aas and 5 or 6 TMSs in a 1 or 2 TMSs (N-terminus) + 2 or 3 TMSs + 1 TMS (C-terminus) arrangement. GluD1 is a signal transduction device disguised as an ionotropic receptor (Dai et al. 2021). GABA rather than L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Delta glutamate receptors have been reported to be functional glycine- and serine-gated cation channels in situ (Carrillo et al. 2021). Clinical features, functional consequences, and rescue pharmacology of missense GRID1 and GRID2 human variants have been described (Allen et al. 2023). GluD1 binds GABA and controls inhibitory plasticity (Piot et al. 2023). Fast synaptic neurotransmission in the vertebrate central nervous system relies primarily on ionotropic glutamate receptors (iGluRs), which drive neuronal excitation, and type A γ-aminobutyric acid receptors (GABAARs), which are responsible for neuronal inhibition. The GluD1 receptor, an iGluR family member, is present at both excitatory and inhibitory synapses. GluD1 binds GABA, and activation produces long-lasting enhancement of GABAergic synaptic currents in the adult mouse hippocampus through a non-ionotropic mechanism that is dependent on trans-synaptic anchoring. The identification of GluD1 as a GABA receptor that controls inhibitory synaptic plasticitywas reported by Piot et al. 2023.
| Eukaryota |
Metazoa, Chordata | GRID1 of Homo sapiens |
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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 |
Cyanobacteriota | GluR0 of Synechocystis sp. PCC6803 |
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1.A.10.2.2 | Probable Ionotropic glutamate receptor (GluR) | Bacteria |
Bacteroidota | GluR homologue of Algoriphagus sp. PR1 (A3I049) |
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1.A.10.2.3 | Probably Ionotropic glutamate receptor (GluR) | Bacteria |
Chlorobiota | GluR homologue of Chlorobium luteolum (Q3B5G3) |
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1.A.10.2.4 | Probable Ionotropic glutamate receptor (GluR) | Bacteria |
Pseudomonadota | GluR homologue of Vibrio fischeri (B5FDH7) |
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1.A.10.2.5 | Uncharacterized protein of 1003 aas and 5 - 7 TMSs | Eukaryota |
Viridiplantae, Chlorophyta | UP of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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1.A.10.3.1 | Ionotropic ligand (glutamate) receptor of 433 aas and 3 or 4 TMSs (Greiner et al. 2018). | Viruses |
Phycodnaviridae | GluR of Paramecium bursaria Chlorella virus IL-3A |
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1.A.10.3.2 | Ligand-gated ion channel of 448 aas and 4 TMSs in a 3 + 1 TMS arrangement. | Viruses |
Bamfordvirae, Nucleocytoviricota | LIC of Only Syngen Nebraska virus 5 |