Abstract
On this planet, the mammalian brain is probably the most complex cellular network. In this system, glutamate is the dominant neurotransmitter, and it mediates the fast communication between the units of the network. Glutamate’s main sites of fast action are the ionotropic glutamate receptors (iGluRs). The iGluRs are a group of receptors that are related in their amino acid sequences and belong to the superfamily of ion channels containing a P-loop as an ion pore. These P-loop channels consist of several subunits. In the case of iGluRs, this subunit assembly is tetrameric. Most iGluRs are associated with auxiliary proteins. The auxiliary proteins can be involved in surface delivery and trafficking of the iGluR, but they can also modulate iGluR channel properties.
The iGluR family consists of four subgroups: AMPA, NMDA, kainate, and orphan receptors, distinguished by their pharmacological profile. The AMPA receptors are directly responsible for the fast signal transmission at synapses, which represents the communication points between the individual neurons. In contrast, the NMDA receptors do not directly participate in fast synaptic transmission; instead, they are the most fundamental modulators of the strength of the synaptic AMPA receptor currents during development and in the mature brain. Together with the AMPA receptors, NMDA receptors keep synapses flexible and thus permit a continuous incorporation or removal of new information into and from the network; in other words, they are necessary for the formation and the extinction of memory. This simple picture of iGluR-mediated neurotransmission is, however, likely to be substantially modified in the future, in view of the great complexity of the iGluR system and its involvement in neurological and neuropsychiatric disorders.
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Abbreviations
- 3D:
-
Three dimensional
- ADAR:
-
Adenosine deaminase acting on RNA
- AMPA:
-
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- ASD:
-
Autism spectrum disorder
- CA1:
-
Cornu Ammonis region 1
- CA3:
-
Cornu Ammonis region 3
- CaMKII:
-
Calmodulin-dependent protein kinase type II
- cDNA:
-
mRNA complementary DNA
- C. elegans :
-
Caenorhabditis elegans
- CKAMP:
-
Cystine-knot AMPA receptor modulating protein
- CNIH:
-
Cornichon homologs
- CNS:
-
Central nervous system
- CUB:
-
Complement C1r/C1s protein domain
- D-AP5:
-
(2R)-Amino-5-phosphonovaleric acid (also known as APV)
- DG:
-
Dentate gyrus
- GABA:
-
(γ-aminobutyric acid)
- GAD:
-
Glutamate decarboxylase
- Gi:
-
Guanine nucleotide-binding protein for inhibiting activating the cAMP-dependent pathway
- GKAP:
-
Guanylate kinase-associated protein
- Gs:
-
Guanine nucleotide-binding protein for activating the cAMP-dependent pathway
- GRIP:
-
Glutamate receptor interacting protein
- ID:
-
Intellectual Disability
- iGluRs:
-
Ionotropic glutamate receptors
- IUPHAR:
-
International Union of Basic and Clinical Pharmacology
- KscA:
-
Potassium channel from Streptomyces lividans
- LBD:
-
Ligand-binding domain
- LGICs:
-
Ligand-gated ion channels
- LTD:
-
Long-term depression
- LTP:
-
Long-term potentiation
- MAGUK:
-
Membrane-associated guanylate kinase
- mGluRs:
-
Metabotropic glutamate receptors
- MWM:
-
Morris water maze
- n-AChR:
-
Nicotinic acetylcholine receptor
- NDE:
-
Near-death experience
- NETO:
-
Neuropilin tolloid-like 1
- NMDA:
-
N-methyl-D-aspartate
- PNDD:
-
Psychiatric and neurodevelopmental disorders
- PhD:
-
Philosophiae doctor
- PKCα:
-
Protein kinase Cα
- PICK1:
-
Protein interacting with C kinase 1
- pre-mRNA:
-
Premature messenger RNA
- PSD:
-
Postsynaptic density
- PSD95:
-
Postsynaptic density proteins 95
- SAP97:
-
Synapse-associated protein 97
- SCZ:
-
Schizophrenia
- SHANK:
-
SH3 and multiple ankyrin repeat domain proteins
- SRM:
-
Spatial reference memory
- SWM:
-
Spatial working memory
- SOL:
-
Suppressor of Lurcher
- Syngap:
-
Synaptic ras GTPase-activating protein
- TARP:
-
Transmembrane AMPA receptor regulatory proteins
- TM:
-
Transmembrane spanning
References
Aarts MM, Arundine M, Tymianski M (2003) Novel concepts in excitotoxic neurodegeneration after stroke. Expert Rev Mol Med 5(30):1–22. https://doi.org/10.1017/S1462399403007087
Akgul G, McBain CJ (2016) Diverse roles for ionotropic glutamate receptors on inhibitory interneurons in developing and adult brain. J Physiol 594(19):5471–5490. https://doi.org/10.1113/JP271764
Bannerman DM, Good MA, Butcher SP, Ramsay M, Morris RG (1995) Distinct components of spatial learning revealed by prior training and NMDA receptor blockade. Nature 378(6553):182–186. https://doi.org/10.1038/378182a0
Bannerman DM, Niewoehner B, Lyon L, Romberg C, Schmitt WB, Taylor A, Sanderson DJ, Cottam J, Sprengel R, Seeburg PH, Kohr G, Rawlins JN (2008) NMDA receptor subunit NR2A is required for rapidly acquired spatial working memory but not incremental spatial reference memory. J Neurosci 28(14):3623–3630. https://doi.org/10.1523/JNEUROSCI.3639-07.2008
Bannerman DM, Sprengel R, Sanderson DJ, McHugh SB, Rawlins JN, Monyer H, Seeburg PH (2014) Hippocampal synaptic plasticity, spatial memory and anxiety. Nat Rev Neurosci 15(3):181–192. https://doi.org/10.1038/nrn3677
Barkus C, Sanderson DJ, Rawlins JN, Walton ME, Harrison PJ, Bannerman DM (2014) What causes aberrant salience in schizophrenia? A role for impaired short-term habituation and the GRIA1 (GluA1) AMPA receptor subunit. Mol Psychiatry 19(10):1060–1070. https://doi.org/10.1038/mp.2014.91
Bertocchi I, Eltokhi A, Rozov A, Chi VN, Jensen V, Bus T, Pawlak V, Serafino M, Sonntag H, Yang B, Burnashev N, Li SB, Obenhaus HA, Both M, Niewoehner B, Single FN, Briese M, Boerner T, Gass P, Rawlins JNP, Kohr G, Bannerman DM, Sprengel R (2021) Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice. Commun Biol 4(1):59. https://doi.org/10.1038/s42003-020-01538-4
Bissen D, Foss F, Acker-Palmer A (2019) AMPA receptors and their minions: auxiliary proteins in AMPA receptor trafficking. Cell Mol Life Sci 76(11):2133–2169. https://doi.org/10.1007/s00018-019-03068-7
Bowie D (2008) Ionotropic glutamate receptors & CNS disorders. CNS Neurol Disord Drug Targets 7(2):129–143. https://doi.org/10.2174/187152708784083821
Boyce-Rustay JM, Holmes A (2006) Genetic inactivation of the NMDA receptor NR2A subunit has anxiolytic- and antidepressant-like effects in mice. Neuropsychopharmacology 31(11):2405–2414. https://doi.org/10.1038/sj.npp.1301039
Brusa R, Zimmermann F, Koh DS, Feldmeyer D, Gass P, Seeburg PH, Sprengel R (1995) Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice. Science 270(5242):1677–1680. https://doi.org/10.1126/science.270.5242.1677
Bygrave AM, Masiulis S, Nicholson E, Berkemann M, Barkus C, Sprengel R, Harrison PJ, Kullmann DM, Bannerman DM, Katzel D (2016) Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801. Transl Psychiatry 6:e778. https://doi.org/10.1038/tp.2016.44
Bygrave AM, Masiulis S, Kullmann DM, Bannerman DM, Katzel D (2018) Gene-environment interaction in a conditional NMDAR-knockout model of schizophrenia. Front Behav Neurosci 12:332. https://doi.org/10.3389/fnbeh.2018.00332
Cain DP, Saucier D, Boon F (1997) Testing hypotheses of spatial learning: the role of NMDA receptors and NMDA-mediated long-term potentiation. Behav Brain Res 84(1–2):179–193. https://doi.org/10.1016/s0166-4328(96)00149-0
Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS, Nicoll RA (2000) Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408(6815):936–943. https://doi.org/10.1038/35050030
Collingridge GL, Olsen RW, Peters J, Spedding M (2009) A nomenclature for ligand-gated ion channels. Neuropharmacology 56(1):2–5. https://doi.org/10.1016/j.neuropharm.2008.06.063
Eltokhi A, Santuy A, Merchan-Perez A, Sprengel R (2020) Glutamatergic dysfunction and synaptic ultrastructural alterations in schizophrenia and autism spectrum disorder: evidence from human and rodent studies. Int J Mol Sci 22(1). https://doi.org/10.3390/ijms22010059
Ge Y, Tian M, Liu L, Wong TP, Gong B, Wu D, Cho T, Lin S, Kast J, Lu J, Wang YT (2019) p97 regulates GluA1 homomeric AMPA receptor formation and plasma membrane expression. Nat Commun 10(1):4089. https://doi.org/10.1038/s41467-019-12096-7
Greger IH, Watson JF, Cull-Candy SG (2017) Structural and functional architecture of AMPA-type glutamate receptors and their auxiliary proteins. Neuron 94(4):713–730. https://doi.org/10.1016/j.neuron.2017.04.009
Jia Z, Agopyan N, Miu P, Xiong Z, Henderson J, Gerlai R, Taverna FA, Velumian A, MacDonald J, Carlen P, Abramow-Newerly W, Roder J (1996) Enhanced LTP in mice deficient in the AMPA receptor GluR2. Neuron 17(5):945–956. https://doi.org/10.1016/s0896-6273(00)80225-1
Jonas P, Racca C, Sakmann B, Seeburg PH, Monyer H (1994) Differences in Ca2+ permeability of AMPA-type glutamate receptor channels in neocortical neurons caused by differential GluR-B subunit expression. Neuron 12(6):1281–1289. https://doi.org/10.1016/0896-6273(94)90444-8
Kask K, Zamanillo D, Rozov A, Burnashev N, Sprengel R, Seeburg PH (1998) The AMPA receptor subunit GluR-B in its Q/R site-unedited form is not essential for brain development and function. Proc Natl Acad Sci U S A 95(23):13777–13782
Kennedy MB (2000) Signal-processing machines at the postsynaptic density. Science 290(5492):750–754. https://doi.org/10.1126/science.290.5492.750
Khan MZ (2019) Ionotropic glutamate receptors (iGluRs) of the delta family (GluD1 and GluD2) and synaptogenesis. Alexandria J Med 53(3):201–206. https://doi.org/10.1016/j.ajme.2016.09.003
Khodosevich K, Jacobi E, Farrow P, Schulmann A, Rusu A, Zhang L, Sprengel R, Monyer H, von Engelhardt J (2014) Coexpressed auxiliary subunits exhibit distinct modulatory profiles on AMPA receptor function. Neuron 83(3):601–615. https://doi.org/10.1016/j.neuron.2014.07.004
Lodge D (2009) The history of the pharmacology and cloning of ionotropic glutamate receptors and the development of idiosyncratic nomenclature. Neuropharmacology 56(1):6–21. https://doi.org/10.1016/j.neuropharm.2008.08.006
Lomo T (2018) Discovering long-term potentiation (LTP) - recollections and reflections on what came after. Acta Physiol (Oxford) 222(2). https://doi.org/10.1111/apha.12921
Mohn AR, Gainetdinov RR, Caron MG, Koller BH (1999) Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98(4):427–436. https://doi.org/10.1016/s0092-8674(00)81972-8
Morris RG, Garrud P, Rawlins JN, O'Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297(5868):681–683. https://doi.org/10.1038/297681a0
Morris RG, Anderson E, Lynch GS, Baudry M (1986) Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319(6056):774–776. https://doi.org/10.1038/319774a0
Nakagawa T, Cheng Y, Ramm E, Sheng M, Walz T (2005) Structure and different conformational states of native AMPA receptor complexes. Nature 433(7025):545–549. https://doi.org/10.1038/nature03328
Nicoll RA, Malenka RC (1995) Contrasting properties of two forms of long-term potentiation in the hippocampus. Nature 377(6545):115–118. https://doi.org/10.1038/377115a0
Park M (2018) AMPA receptor trafficking for postsynaptic potentiation. Front Cell Neurosci 12(361):361. https://doi.org/10.3389/fncel.2018.00361
Reiner A, Levitz J (2018) Glutamatergic signaling in the central nervous system: ionotropic and metabotropic receptors in concert. Neuron 98(6):1080–1098. https://doi.org/10.1016/j.neuron.2018.05.018
Salpietro V, Dixon CL, Guo H, Bello OD, Vandrovcova J, Efthymiou S, Maroofian R, Heimer G, Burglen L, Valence S, Torti E, Hacke M, Rankin J, Tariq H, Colin E, Procaccio V, Striano P, Mankad K, Lieb A, Chen S, Pisani L, Bettencourt C, Mannikko R, Manole A, Brusco A, Grosso E, Ferrero GB, Armstrong-Moron J, Gueden S, Bar-Yosef O, Tzadok M, Monaghan KG, Santiago-Sim T, Person RE, Cho MT, Willaert R, Yoo Y, Chae JH, Quan Y, Wu H, Wang T, Bernier RA, Xia K, Blesson A, Jain M, Motazacker MM, Jaeger B, Schneider AL, Boysen K, Muir AM, Myers CT, Gavrilova RH, Gunderson L, Schultz-Rogers L, Klee EW, Dyment D, Osmond M, Parellada M, Llorente C, Gonzalez-Penas J, Carracedo A, Van Haeringen A, Ruivenkamp C, Nava C, Heron D, Nardello R, Iacomino M, Minetti C, Skabar A, Fabretto A, Group SS, Raspall-Chaure M, Chez M, Tsai A, Fassi E, Shinawi M, Constantino JN, De Zorzi R, Fortuna S, Kok F, Keren B, Bonneau D, Choi M, Benzeev B, Zara F, Mefford HC, Scheffer IE, Clayton-Smith J, Macaya A, Rothman JE, Eichler EE, Kullmann DM, Houlden H (2019) AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders. Nat Commun 10(1):3094. https://doi.org/10.1038/s41467-019-10910-w
Scheefhals N, MacGillavry HD (2018) Functional organization of postsynaptic glutamate receptors. Mol Cell Neurosci 91:82–94. https://doi.org/10.1016/j.mcn.2018.05.002
Schmid SM, Hollmann M (2008) To gate or not to gate: are the delta subunits in the glutamate receptor family functional ion channels? Mol Neurobiol 37(2–3):126–141. https://doi.org/10.1007/s12035-008-8025-0
Schwenk J, Harmel N, Zolles G, Bildl W, Kulik A, Heimrich B, Chisaka O, Jonas P, Schulte U, Fakler B, Klocker N (2009) Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science 323(5919):1313–1319. https://doi.org/10.1126/science.1167852
Seeburg PH (1996) The role of RNA editing in controlling glutamate receptor channel properties. J Neurochem 66(1):1–5. https://doi.org/10.1046/j.1471-4159.1996.66010001.x
Single FN, Rozov A, Burnashev N, Zimmermann F, Hanley DF, Forrest D, Curran T, Jensen V, Hvalby O, Sprengel R, Seeburg PH (2000) Dysfunctions in mice by NMDA receptor point mutations NR1(N598Q) and NR1(N598R). J Neurosci 20(7):2558–2566
Sobolevsky AI, Rosconi MP, Gouaux E (2009) X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462(7274):745–756. https://doi.org/10.1038/nature08624
Soto D, Altafaj X, Sindreu C, Bayes A (2014) Glutamate receptor mutations in psychiatric and neurodevelopmental disorders. Commun Integr Biol 7(1):e27887. https://doi.org/10.4161/cib.27887
Sprengel R (2006) Role of AMPA receptors in synaptic plasticity. Cell Tissue Res 326(2):447–455. https://doi.org/10.1007/s00441-006-0275-4
Sprengel R, Suchanek B, Amico C, Brusa R, Burnashev N, Rozov A, Hvalby O, Jensen V, Paulsen O, Andersen P, Kim JJ, Thompson RF, Sun W, Webster LC, Grant SG, Eilers J, Konnerth A, Li J, McNamara JO, Seeburg PH (1998) Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell 92(2):279–289. https://doi.org/10.1016/s0092-8674(00)80921-6
Sprengel R, Aronoff R, Volkner M, Schmitt B, Mosbach R, Kuner T (2001) Glutamate receptor channel signatures. Trends Pharmacol Sci 22(1):7–10. https://doi.org/10.1016/s0165-6147(00)01588-1
Sprengel R, Eltokhi A, Single FN (2017) Gene targeted mice with conditional knock-in (-out) of NMDAR mutations. Methods Mol Biol 1677:201–230. https://doi.org/10.1007/978-1-4939-7321-7_11
Sun HY, Bartley AF, Dobrunz LE (2009) Calcium-permeable presynaptic kainate receptors involved in excitatory short-term facilitation onto somatostatin interneurons during natural stimulus patterns. J Neurophysiol 101(2):1043–1055. https://doi.org/10.1152/jn.90286.2008
Tikhonov DB, Magazanik LG (2009) Origin and molecular evolution of ionotropic glutamate receptors. Neurosci Behav Physiol 39(8):763–773. https://doi.org/10.1007/s11055-009-9195-6
Tomita S, Castillo PE (2012) Neto1 and Neto2: auxiliary subunits that determine key properties of native kainate receptors. J Physiol 590(10):2217–2223. https://doi.org/10.1113/jphysiol.2011.221101
Tsien JZ, Chen DF, Gerber D, Tom C, Mercer EH, Anderson DJ, Mayford M, Kandel ER, Tonegawa S (1996a) Subregion- and cell type-restricted gene knockout in mouse brain. Cell 87(7):1317–1326. https://doi.org/10.1016/s0092-8674(00)81826-7
Tsien JZ, Huerta PT, Tonegawa S (1996b) The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87(7):1327–1338. https://doi.org/10.1016/s0092-8674(00)81827-9
Vissel B, Royle GA, Christie BR, Schiffer HH, Ghetti A, Tritto T, Perez-Otano I, Radcliffe RA, Seamans J, Sejnowski T, Wehner JM, Collins AC, O'Gorman S, Heinemann SF (2001) The role of RNA editing of kainate receptors in synaptic plasticity and seizures. Neuron 29(1):217–227. https://doi.org/10.1016/s0896-6273(01)00192-1
Wyeth MS, Pelkey KA, Yuan X, Vargish G, Johnston AD, Hunt S, Fang C, Abebe D, Mahadevan V, Fisahn A, Salter MW, McInnes RR, Chittajallu R, McBain CJ (2017) Neto auxiliary subunits regulate interneuron somatodendritic and presynaptic Kainate receptors to control network inhibition. Cell Rep 20(9):2156–2168. https://doi.org/10.1016/j.celrep.2017.08.017
Zamanillo D, Sprengel R, Hvalby O, Jensen V, Burnashev N, Rozov A, Kaiser KM, Koster HJ, Borchardt T, Worley P, Lubke J, Frotscher M, Kelly PH, Sommer B, Andersen P, Seeburg PH, Sakmann B (1999) Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284(5421):1805–1811. https://doi.org/10.1126/science.284.5421.1805
Zheng Y, Brockie PJ, Mellem JE, Madsen DM, Walker CS, Francis MM, Maricq AV (2006) SOL-1 is an auxiliary subunit that modulates the gating of GLR-1 glutamate receptors in Caenorhabditis elegans. Proc Natl Acad Sci U S A 103(4):1100–1105. https://doi.org/10.1073/pnas.0504612103
Zhou Q, Sheng M (2013) NMDA receptors in nervous system diseases. Neuropharmacology 74:69–75. https://doi.org/10.1016/j.neuropharm.2013.03.030
Zuo J, De Jager PL, Takahashi KA, Jiang W, Linden DJ, Heintz N (1997) Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene. Nature 388(6644):769–773. https://doi.org/10.1038/42009
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Sprengel, R., Eltokhi, A. (2022). Ionotropic Glutamate Receptors (and Their Role in Health and Disease). In: Pfaff, D.W., Volkow, N.D., Rubenstein, J.L. (eds) Neuroscience in the 21st Century. Springer, Cham. https://doi.org/10.1007/978-3-030-88832-9_4
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