AMPA Receptors


Neuronal communication relies on rapid signalling via chemical synapses. Glutamate receptors mediate the majority of excitatory neurotransmission in the central nervous system. At excitatory synapses, glutamate is released and binds to a variety of glutamate receptors. Among these, α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) receptors mediate most of the fast excitatory synaptic transmission. In addition, AMPA receptors play a critical role in the synaptic plasticity underlying learning and memory and neuronal development. When the regulation of synaptic expression of AMPA receptors goes awry, devastating neurological and neuropsychiatric diseases can occur. Since their cloning in the 1990s, much has been learned about the structure, assembly and trafficking of AMPA receptors. Exciting new advances in AMPA receptor research have offered unprecedented opportunities to understand dynamic regulation of AMPA receptor structure and function in brain.

Key Concepts:

  • AMPA receptors mediate fast glutamatergic synaptic transmission.

  • Crystal structure of AMPA receptors shows unexpected domain organisation.

  • Regulation of synaptic expression of AMPA receptors is highly dynamic.

  • AMPA receptor modulation and/or trafficking mediates LTP.

  • AMPA receptors are structurally diverse.

  • Subunit composition of AMPA receptors varies at different synapses.

  • Post‐translational modifications of AMPA receptors regulate trafficking and function.

  • AMPA receptor dysfunction is involved in diseases.

Keywords: glutamate; AMPA receptor; excitatory synapse; crystal structure; receptor phosphorylation; palmitoylation; ubiquitination; synaptic plasticity; receptor trafficking; stargazin; cornichon; AMPAKines

Figure 1.

Topologies of the AMPA receptor and its auxiliary subunits. Schematics of an AMPA receptor subunit in the plasma membrane (left), transmembrane AMPA receptor regulatory protein (TARP, middle) and cornichon (CNIH, right). NTD, extracellular ligand‐binding domains (S1 and S2), transmembrane domains, the flip/flop alternative splicing site and the RNA‐editing sites (Q/R and R/G) are also shown for the AMPA receptor. Figure adapted from Jackson and Nicoll . © Elsevier.

Figure 2.

Schematic of an AMPA receptor. AMPA receptors are tetrameric cation channels composed of various combinations of different subunits. Note that membrane region 2 (M2) is a reentrant loop, not a transmembrane domain, that underlies the channel pore formation.



Alt A, Nisenbaum ES, Bleakman D and Witkin JM (2006) A role for AMPA receptors in mood disorders. Biochemical Pharmacology 71: 1273–1288.

Andrews PI and McNamara JO 1996. Rasmussen's encephalitis: an autoimmune disorder? Current Opinion in Neurobiology 6: 673–678.

Anggono V and Huganir RL (2012) Regulation of AMPA receptor trafficking and synaptic plasticity. Current Opinion in Neurobiology 22: 461–469.

Black MD (2005) Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data. Psychopharmacology 179: 154–163.

Blanpied TA, Scott DB and Ehlers MD (2002) Dynamics and regulation of clathrin coats at specialized endocytic zones of dendrites and spines. Neuron 36: 435–449.

Bliss TV and Collingridge GL (1993) A synaptic model of memory: long‐term potentiation in the hippocampus. Nature 361: 31–39.

Borges K and Dingledine R (1998) AMPA receptors: molecular and functional diversity. Progress in Brain Research 116: 153–170.

Boyle J, Stanley N, James LM et al. (2012) Acute sleep deprivation: the effects of the AMPAKINE compound CX717 on human cognitive performance, alertness and recovery sleep. Journal of Psychopharmacology 26: 1047–1057.

Chang PK, Verbich D and Mckinney RA (2012) AMPA receptors as drug targets in neurological disease – advantages, caveats, and future outlook. European Journal of Neuroscience 35: 1908–1916.

Chen L, Chetkovich DM, Petralia RS et al. (2000) Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408: 936–943.

Cull‐Candy S, Kelly L and Farrant M (2006) Regulation of Ca2+‐permeable AMPA receptors: synaptic plasticity and beyond. Current Opinion in Neurobiology 16: 288–297.

Dong H, O'brien RJ, Fung ET et al. (1997) GRIP: a synaptic PDZ domain‐containing protein that interacts with AMPA receptors. Nature 386: 279–284.

Fu AK, Hung KW, Fu WY et al. (2011) APC(Cdh1) mediates EphA4‐dependent downregulation of AMPA receptors in homeostatic plasticity. Nature Neuroscience 14: 181–189.

Granger AJ, Shi Y, Lu W, Cerpas M and Nicoll RA (2013) LTP requires a reserve pool of glutamate receptors independent of subunit type. Nature 493: 495–500.

Hayashi T, Rumbaugh G and Huganir RL (2005) Differential regulation of AMPA receptor subunit trafficking by palmitoylation of two distinct sites. Neuron 47: 709–723.

Herring BE, Shi Y, Suh YH et al. (2013) Cornichon proteins determine the subunit composition of synaptic AMPA receptors. Neuron 77: 1083–1096.

Hollmann M and Heinemann S (1994) Cloned glutamate receptors. Annual Review of Neuroscience 17: 31–108.

Hume RI, Dingledine R and Heinemann SF (1991) Identification of a site in glutamate receptor subunits that controls calcium permeability. Science 253: 1028–1031.

Isaac JT (2003) Postsynaptic silent synapses: evidence and mechanisms. Neuropharmacology 45: 450–460.

Isaac JT, Ashby MC and Mcbain CJ (2007) The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity. Neuron 54: 859–871.

Isaac JT, Nicoll RA and Malenka RC (1995) Evidence for silent synapses: implications for the expression of LTP. Neuron 15: 427–434.

Jackson AC and Nicoll RA (2011) The expanding social network of ionotropic glutamate receptors: TARPs and other transmembrane auxiliary subunits. Neuron 70: 178–199.

Jurado S, Goswami D, Zhang Y et al. (2013) LTP requires a unique postsynaptic SNARE fusion machinery. Neuron 77: 542–558.

Kumar J and Mayer ML (2013) Functional insights from glutamate receptor ion channel structures. Annual Review of Physiology 75: 313–337.

Lee HK (2006) Synaptic plasticity and phosphorylation. Pharmacology & Therapeutics 112: 810–832.

Lee SH, Liu L, Wang YT and Sheng M (2002) Clathrin adaptor AP2 and NSF interact with overlapping sites of GluR2 and play distinct roles in AMPA receptor trafficking and hippocampal LTD. Neuron 36: 661–674.

Liao D, Hessler NA and Malinow R (1995) Activation of postsynaptically silent synapses during pairing‐induced LTP in CA1 region of hippocampal slice. Nature 375: 400–404.

Lin A, Hou Q, Jarzylo L et al. (2011) Nedd4‐mediated AMPA receptor ubiquitination regulates receptor turnover and trafficking. Journal of Neurochemistry 119: 27–39.

Lin DT, Makino Y, Sharma K et al. (2009) Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation. Nature Neuroscience 12: 879–887.

Lledo PM, Zhang X, Sudhof TC, Malenka RC and Nicoll RA (1998) Postsynaptic membrane fusion and long‐term potentiation. Science 279: 399–403.

Lomeli H, Mosbacher J, Melcher T et al. (1994) Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science 266: 1709–1713.

Lu W, Isozaki K, Roche KW and Nicoll RA (2010) Synaptic targeting of AMPA receptors is regulated by a CaMKII site in the first intracellular loop of GluA1. Proceedings of the National Academy of Sciences of the USA 107: 22266–22271.

Lu W and Roche KW (2012) Posttranslational regulation of AMPA receptor trafficking and function. Current Opinion in Neurobiology 22: 470–479.

Lu W, Shi Y, Jackson AC et al. (2009) Subunit composition of synaptic AMPA receptors revealed by a single‐cell genetic approach. Neuron 62: 254–268.

Lussier MP, Nasu‐Nishimura Y and Roche KW (2011) Activity‐dependent ubiquitination of the AMPA receptor subunit GluA2. Journal of Neuroscience 31: 3077–3081.

Malenka RC and Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44: 5–21.

Mayer ML and Westbrook GL (1984) Mixed‐agonist action of excitatory amino acids on mouse spinal cord neurones under voltage clamp. Journal of Physiology 354: 29–53.

Nations KR, Dogterom P, Bursi R et al. (2012) Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double‐blind, placebo‐controlled trial. Journal of Psychopharmacology 26: 1525–1539.

Newpher TM and Ehlers MD (2008) Glutamate receptor dynamics in dendritic microdomains. Neuron 58: 472–497.

Opazo P and Choquet D (2011) A three‐step model for the synaptic recruitment of AMPA receptors. Molecular and Cellular Neuroscience 46: 1–8.

Park M, Penick EC, Edwards JG, Kauer JA and Ehlers MD (2004) Recycling endosomes supply AMPA receptors for LTP. Science 305: 1972–1975.

Roche KW, O'brien RJ, Mammen AL, Bernhardt J and Huganir RL (1996) Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit. Neuron 16: 1179–1188.

Schwarz LA, Hall BJ and Patrick GN (2010) Activity‐dependent ubiquitination of GluA1 mediates a distinct AMPA receptor endocytosis and sorting pathway. Journal of Neuroscience 30: 16718–16729.

Schwenk J, Harmel N, Zolles G et al. (2009) Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science 323: 1313–1319.

Sobolevsky AI, Rosconi MP and Gouaux E (2009) X‐ray structure, symmetry and mechanism of an AMPA‐subtype glutamate receptor. Nature 462: 745–756.

Sommer B, Keinanen K, Verdoorn TA et al. (1990) Flip and flop: a cell‐specific functional switch in glutamate‐operated channels of the CNS. Science 249: 1580–1585.

Sommer B, Kohler M, Sprengel R and Seeburg PH (1991) RNA editing in brain controls a determinant of ion flow in glutamate‐gated channels. Cell 67: 11–19.

Srivastava S, Osten P, Vilim FS et al. (1998) Novel anchorage of GluR2/3 to the postsynaptic density by the AMPA receptor‐binding protein ABP. Neuron 21: 581–591.

Traynelis SF, Wollmuth LP, Mcbain CJ et al. (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacological Reviews 62: 405–496.

Walker CS, Brockie PJ, Madsen DM et al. (2006) Reconstitution of invertebrate glutamate receptor function depends on stargazin‐like proteins. Proceedings of the National Academy of Sciences of the USA 103: 10781–10786.

Watkins JC and Evans RH (1981) Excitatory amino acid transmitters. Annual Review of Pharmacology and Toxicology 21: 165–204.

Wisden W and Seeburg PH (1993) Mammalian ionotropic glutamate receptors. Current Opinion in Neurobiology 3: 291–298.

Yang G, Xiong W, Kojic L and Cynader MS (2009) Subunit‐selective palmitoylation regulates the intracellular trafficking of AMPA receptor. European Journal of Neuroscience 30: 35–46.

Zheng Y, Mellem JE, Brockie PJ, Madsen DM and Maricq AV (2004) SOL‐1 is a CUB‐domain protein required for GLR‐1 glutamate receptor function in C. elegans. Nature 427: 451–457.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Lu, Wei, and Roche, Katherine W(Dec 2013) AMPA Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000231.pub3]