Abstract
AMPA receptors are ionotropic glutamate receptors that mediate the majority of fast excitatory transmission in the central nervous system. Their function depends not only on the composition of the subunits GluA1-4, but also on the interaction with auxiliary subunits. Several auxiliary subunits have been identified in proteomic analyses over the last years and we are beginning to understand the complex control of these proteins on physiological properties and membrane-transport of AMPA receptors. Auxiliary subunits such as TARPs, cornichons, and CKAMP44 influence receptor localization on the cell membrane, modulate receptor gating, and play a role for synaptic short-term and long-term plasticity.
Similar content being viewed by others
References
Boulter J et al (1990) Molecular cloning and functional expression of glutamate receptor subunit genes. Science 249:1033–1037
Keinanen K et al (1990) A family of AMPA-selective glutamate receptors. Science 249:556–560
Hollmann M, Hartley M, Heinemann S (1991) Ca2+ permeability of KA-AMPA–gated glutamate receptor channels depends on subunit composition. Science 252:851–853
Lomeli H et al (1994) Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science 266:1709–1713
Mosbacher J et al (1994) A molecular determinant for submillisecond desensitization in glutamate receptors. Science 266:1059–1062
Partin KM, Patneau DK, Mayer ML (1994) Cyclothiazide differentially modulates desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor splice variants. Mol Pharmacol 46:129–138
Sekiguchi M et al (1997) A novel allosteric potentiator of AMPA receptors: 4–2-(phenylsulfonylamino)ethylthio–2,6-difluoro-phenoxyaceta mide. J Neurosci 17:5760–5771
Sommer B et al (1990) Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS. Science 249:1580–1585
Burnashev N, Monyer H, Seeburg PH, Sakmann B (1992) Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit. Neuron 8:189–198
Nakanishi N, Shneider NA, Axel R (1990) A family of glutamate receptor genes: evidence for the formation of heteromultimeric receptors with distinct channel properties. Neuron 5:569–581
Verdoorn TA, Burnashev N, Monyer H, Seeburg PH, Sakmann B (1991) Structural determinants of ion flow through recombinant glutamate receptor channels. Science 252:1715–1718
Rosenthal JJC, Seeburg PH (2012) A-to-I RNA Editing: effects on proteins key to neural excitability. Neuron 74:432–439
Monyer H, Seeburg PH, Wisden W (1991) Glutamate-operated channels—developmentally early and mature forms arise by alternative splicing. Neuron 6:799–810
Tomita S et al (2003) Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins. J Cell Biol 161:805–816
Tomita S, Stein V, Stocker TJ, Nicoll RA, Bredt DS (2005) Bidirectional synaptic plasticity regulated by phosphorylation of stargazin-like TARPs. Neuron 45:269–277
Chen L, Bao S, Qiao X, Thompson RF (1999) Impaired cerebellar synapse maturation in waggler, a mutant mouse with a disrupted neuronal calcium channel gamma subunit. Proc Natl Acad Sci USA 96:12132–12137
Hashimoto K et al (1999) Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer. J Neurosci 19:6027–6036
Kang MG et al (2012) Proteomic analysis of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor complexes. J Biol Chem 287:28632–28645
Schwenk J et al (2012) High-resolution proteomics unravel architecture and molecular diversity of native AMPA receptor complexes. Neuron 74:621–633
Schwenk J et al (2009) Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science 323:1313–1319
Shanks NF et al (2012) Differences in AMPA and kainate receptor interactomes facilitate identification of AMPA receptor auxiliary subunit GSG1 L. Cell Rep 1:590–598
von Engelhardt J et al (2010) CKAMP44: a brain-specific protein attenuating short-term synaptic plasticity in the dentate gyrus. Science 327:1518–1522
Yan D, Tomita S (2012) Defined criteria for auxiliary subunits of glutamate receptors. J Physiol 590:21–31
Kalashnikova E et al (2010) SynDIG1: an activity-regulated, AMPA- receptor-interacting transmembrane protein that regulates excitatory synapse development. Neuron 65:80–93
Lovero KL, Blankenship SM, Shi Y, Nicoll RA (2013) SynDIG1 promotes excitatory synaptogenesis independent of AMPA receptor trafficking and biophysical regulation. PLoS One 8:e66171
Copits BA, Robbins JS, Frausto S, Swanson GT (2011) Synaptic targeting and functional modulation of GluK1 kainate receptors by the auxiliary neuropilin and tolloid-like (NETO) proteins. J Neurosci 31:7334–7340
Ng D et al (2009) Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning. PloS Biol 7:278–300
Straub C et al (2011) Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1. Nat Neurosci 14:866-U883
Straub C, Zhang W, Howe JR (2011) Neto2 modulation of kainate receptors with different subunit compositions. J Neuroscience 31:8078–8082
Tang M et al (2011) Neto1 is an auxiliary subunit of native synaptic kainate receptors. J Neurosci 31:10009–10018
Zhang W et al (2009) A Transmembrane accessory subunit that modulates kainate-type glutamate receptors. Neuron 61:385–396
Schwenk J et al (2010) Native GABA(B) receptors are heteromultimers with a family of auxiliary subunits. Nature 465:231-U121
Turecek R et al (2014) Auxiliary GABA(B) receptor subunits uncouple G protein beta gamma subunits from effector channels to induce desensitization. Neuron 82:1032–1044
Brockie PJ et al (2013) Cornichons control ER export of AMPA receptors to regulate synaptic excitability. Neuron 80:129–142
Walker CS et al (2006) Reconstitution of invertebrate glutamate receptor function depends on stargazin-like proteins. Proc Natl Acad Sci USA 103:10781–10786
Walker CS et al (2006) Conserved SOL-1 proteins regulate ionotropic glutamate receptor desensitization. Proc Natl Acad Sci USA 103:10787–10792
Wang R et al (2012) The SOL-2/Neto auxiliary protein modulates the function of AMPA-subtype ionotropic glutamate receptors. Neuron 75:838–850
Wang R et al (2008) Evolutionary conserved role for TARPs in the gating of glutamate receptors and tuning of synaptic function. Neuron 59:997–1008
Zheng Y et al (2006) SOL-1 is an auxiliary subunit that modulates the gating of GLR-1 glutamate receptors in Caenorhabditis elegans. Proc Natl Acad Sci USA 103:1100–1105
Zheng Y, Mellem JE, Brockie PJ, Madsen DM, Maricq AV (2004) SOL-1 is a CUB-domain protein required for GLR-1 glutamate receptor function in C. elegans. Nature 427:451–457
Boulin T et al (2012) Positive modulation of a Cys-loop acetylcholine receptor by an auxiliary transmembrane subunit. Nat Neurosci 15:1374–1381
Vacher H, Mohapatra DP, Trimmer JS (2008) Localization and targeting of voltage-dependent ion channels in mammalian central neurons. Physiol Rev 88:1407–1447
Burgess DL, Gefrides LA,Foreman PJ, Noebels JL (2001) A cluster of three novel Ca2 + channel gamma subunit genes on chromosome 19q13.4: evolution and expression profile of the gamma subunit gene family. Genomics 71:339–350
Kato AS, Gill MB, Yu H, Nisenbaum ES, Bredt DS (2010) TARPs differentially decorate AMPA receptors to specify neuropharmacology. Trends Neurosci 33:241–248
Kato AS, Siuda ER, Nisenbaum ES, Bredt DS (2008) AMPA receptor subunit-specific regulation by a distinct family of type II TARPs. Neuron 59:986–996
Kato AS et al (2007) New transmembrane AMPA receptor regulatory protein isoform, gamma-7, differentially regulates AMPA receptors. J Neurosci 27:4969–4977
Klugbauer N et al (2000) A family of gamma-like calcium channel subunits. Febs Lett 470:189–197
Kim KS, Yan D, Tomita S (2010) Assembly and Stoichiometry of the AMPA Receptor and Transmembrane AMPA Receptor Regulatory Protein Complex. J Neurosci 30:1064–1072
Shi Y, Lu W, Milstein AD, Nicoll RA (2009) The stoichiometry of AMPA receptors and TARPs varies by neuronal cell type. Neuron 62:633–640
Fukaya M, Yamazaki M, Sakimura K, Watanabe M (2005) Spatial diversity in gene expression for VDCCgamma subunit family in developing and adult mouse brains. Neurosci Res 53:376–383
Bokel C, Dass S, Wilsch-Brauninger M, Roth S (2006) Drosophila Cornichon acts as cargo receptor for ER export of the TGF alpha-like growth factor Gurken. Development 133:459–470
Castro CP, Piscopo D, Nakagawa T, Derynck R (2007) Cornichon regulates transport and secretion of TGF alpha-related proteins in metazoan cells. J Cell Sci 120:2454–2466
Hoshino H et al (2007) Cornichon-like protein facilitates secretion of HB-EGF and regulates proper development of cranial nerves. Mol Biol Cell 18:1143–1152
Powers J, Barlowe C (1998) Transport of axl2p depends on erv14p, an ER-vesicle protein related to the Drosophila cornichon gene product. J Cell Biol 142:1209–1222
Powers J, Barlowe C (2002) Erv14p directs a transmembrane secretory protein into COPII-coated transport vesicles. Mol Biol Cell 13:880–891
Harmel N et al (2012) AMPA receptors commandeer an ancient cargo exporter for use as an auxiliary subunit for signaling. PLoS One 7:e30681
Shi Y et al (2010) Functional comparison of the effects of TARPs and cornichons on AMPA receptor trafficking and gating. Proc Natl Acad Sci USA 107:16315–16319
Herring BE et al (2013) Cornichon proteins determine the subunit composition of synaptic AMPA receptors. Neuron 77:1083–1096
Boudkkazi S, Brechet A, Schwenk J, Fakler B (2014) Cornichon2 dictates the time course of excitatory transmission at individual hippocampal synapses. Neuron 82:848–858
Gill MB et al (2011) Cornichon-2 modulates AMPA receptor-transmembrane AMPA receptor regulatory protein assembly to dictate gating and pharmacology. J Neurosci 31:6928–6938
Kato AS et al (2010) Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins. Neuron 68:1082–1096
Mauric V et al (2013) Ontogeny repeats the phylogenetic recruitment of the cargo exporter cornichon into AMPA receptor signaling complexes. Mol Cell Neurosci 56:10–17
Khodosevich K et al (2014) Coexpressed auxiliary subunits exhibit distinct modulatory profiles on AMPA receptor function. Neuron 83:601–615
Schwenk J et al (2014) Regional diversity and developmental dynamics of the AMPA-receptor proteome in the mammalian brain. Neuron 84:41–54
Chen L et al (2000) Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408:936–943
Cho CH, St-Gelais F, Zhang W, Tomita S, Howe JR (2007) Two families of TARP isoforms that have distinct effects on the kinetic properties of AMPA receptors and synaptic currents. Neuron 55:890–904
Coombs ID et al (2012) Cornichons modify channel properties of recombinant and glial AMPA receptors. J Neurosci 32:9796–9804
Gill MB, Kato AS, Wang H, Bredt DS (2012) AMPA receptor modulation by cornichon-2 dictated by transmembrane AMPA receptor regulatory protein isoform. Eur J Neurosci 35:182–194
Kott S, Sager C, Tapken D, Werner M, Hollmann M (2009) Comparative analysis of the pharmacology of GluR1 in complex with transmembrane AMPA receptor regulatory proteins gamma2, gamma3, gamma4, and gamma8. Neuroscience 158:78–88
Letts VA et al (1998) The mouse stargazer gene encodes a neuronal Ca2+ -channel gamma subunit. Nat Genet 19:340–347
Milstein AD, Zhou W, Karimzadegan S, Bredt DS, Nicoll RA (2007) TARP subtypes differentially and dose-dependently control synaptic AMPA receptor gating. Neuron 55:905–918
Priel A et al (2005) Stargazin reduces desensitization and slows deactivation of the AMPA-type glutamate receptors. J Neurosci 25:2682–2686
Soto D, Coombs ID, Kelly L, Farrant M, Cull-Candy.SG (2007) Stargazin attenuates intracellular polyamine block of calcium-permeable AMPA receptors. Nat Neurosci 10:1260–1267
Soto D et al (2009) Selective regulation of long-form calcium-permeable AMPA receptors by an atypical TARP, gamma-5. Nat Neurosci 12:277–285
Turetsky D, Garringer E, Patneau DK (2005) Stargazin modulates native AMPA receptor functional properties by two distinct mechanisms. J Neurosci 25:7438–7448
Ziff EB (2007) TARPs and the AMPA receptor trafficking paradox. Neuron 53:627–633
Rouach N et al (2005) TARP gamma-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity. Nat Neurosci 8:1525–1533
Bats C, Soto D, Studniarczyk D, Farrant M, Cull-Candy SG (2012) Channel properties reveal differential expression of TARPed and TARPless AMPARs in stargazer neurons. Nat Neurosci 15:853–861
Jackson AC, Nicoll RA (2011) Stargazin (TARP gamma-2) is required for compartment-specific AMPA receptor trafficking and synaptic plasticity in cerebellar stellate cells. J Neurosci 31:3939–3952
Menuz K, Kerchner GA, O’Brien JL, Nicoll RA (2009) Critical role for TARPs in early development despite broad functional redundancy. Neuropharmacology 56:22–29
Menuz K, Nicoll RA (2008) Loss of inhibitory neuron AMPA receptors contributes to ataxia and epilepsy in stargazer mice. J Neurosci 28:10599–10603
Trussell LO, Zhang S, Raman IM (1993) Desensitization of AMPA receptors upon multiquantal neurotransmitter release. Neuron 10:1185–1196
Menuz K, O’Brien JL, Karmizadegan S, Bredt DS, Nicoll RA (2008) TARP redundancy is critical for maintaining AMPA receptor function. J Neurosci 28:8740–8746
Tomita S et al (2005) Stargazin modulates AMPA receptor gating and trafficking by distinct domains. Nature 435:1052–1058
Greger IH, Ziff EB, Penn AC (2007) Molecular determinants of AMPA receptor subunit assembly. Trends Neurosci 30:407–416
Greger IH, Akamine P, Khatri L, Ziff EB (2006) Developmentally regulated, combinatorial RNA processing modulates AMPA receptor biogenesis. Neuron 51:85–97
Penn AC, Williams SR, Greger IH (2008) Gating motions underlie AMPA receptor secretion from the endoplasmic reticulum. EMBO J 27:3056–3068
Sumioka A, Yan D, Tomita S (2010) TARP phosphorylation regulates synaptic AMPA receptors through lipid bilayers. Neuron 66:755–767
Opazo P et al (2010) CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin. Neuron 67:239–252
Nomura T et al (2012) Cerebellar long-term depression requires dephosphorylation of TARP in Purkinje cells. Eur J Neurosci 35:402–410
Sumioka A et al (2011) PDZ binding of TARPgamma-8 controls synaptic transmission but not synaptic plasticity. Nat Neurosci 14:1410–1412
Heine M et al (2008) Surface mobility of postsynaptic AMPARs tunes synaptic transmission. Science 320:201–205
Constals A et al (2015) Glutamate-Induced AMPA Receptor Desensitization Increases Their Mobility and Modulates Short-Term Plasticity through Unbinding from Stargazin. Neuron 85:787–803
Lissin DV et al (1998) Activity differentially regulates the surface expression of synaptic AMPA and NMDA glutamate receptors. Proc Natl Acad Sci U S A 95:7097–7102
O’Brien RJ et al (1998) Activity-dependent modulation of synaptic AMPA receptor accumulation. Neuron 21:1067–1078
Turrigiano GG, Leslie KR, Desai NS, Rutherford LC, Nelson SB (1998) Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391:892–896
Everett K et al (2007) Linkage and mutational analysis of CLCN2 in childhood absence epilepsy. Epilepsy Res 75:145–153
Knight HM et al (2008) Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment. Eur J Hum Genet 16:750–758
Liu YL et al (2008) RASD2, MYH9, and CACNG2 genes at chromosome 22q12 associated with the subgroup of schizophrenia with non-deficit in sustained attention and executive function. Biol Psychiatry 64:789–796
Silberberg G et al (2008) Stargazin involvement with bipolar disorder and response to lithium treatment. Pharmacogenet Genomics 18:403–412
Wilson GM et al (2006) DNA copy-number analysis in bipolar disorder and schizophrenia reveals aberrations in genes involved in glutamate signaling. Hum Mol Genet 15:743–749
Acknowledgments
This work has been funded by the German Research Foundation (DFG) within the Collaborative Research Center (SFB) 1134 “Functional Ensembles” and the Research Grant EN948/1–1. We would like to thank Dagmar Anders from the DKFZ and Eric Jacobi for the generation of the figures.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Monyer, H., von Engelhardt, J. Modulation of AMPA receptor function by auxiliary subunits. e-Neuroforum 6, 39–48 (2015). https://doi.org/10.1007/s13295-015-0005-z
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13295-015-0005-z