Architecture and Subunit Arrangement of Native AMPA Receptors Elucidated by Cryo-EM

Overview

Journal Science

Specialty Science

Date 2019 Apr 13

PMID 30975770

Citations 82

Authors

Yan Zhao

Shanshuang Chen

Adam C Swensen

Wei-Jun Qian

Eric Gouaux

Affiliations

Soon will be listed here.

Abstract

Glutamate-gated AMPA receptors mediate the fast component of excitatory signal transduction at chemical synapses throughout all regions of the mammalian brain. AMPA receptors are tetrameric assemblies composed of four subunits, GluA1-GluA4. Despite decades of study, the subunit composition, subunit arrangement, and molecular structure of native AMPA receptors remain unknown. Here we elucidate the structures of 10 distinct native AMPA receptor complexes by single-particle cryo-electron microscopy (cryo-EM). We find that receptor subunits are arranged nonstochastically, with the GluA2 subunit preferentially occupying the B and D positions of the tetramer and with triheteromeric assemblies comprising a major population of native AMPA receptors. Cryo-EM maps define the structure for S2-M4 linkers between the ligand-binding and transmembrane domains, suggesting how neurotransmitter binding is coupled to ion channel gating.

Citing Articles

A Scoping Review of Corticosterone-Induced Changes in Ionotropic Glutamate Receptor Levels and Localization in the Rodent Brain: Implications for the Auditory System.

Edlund E, Domarecka E, Olze H, Szczepek A Brain Sci. 2025; 15(2).

PMID: 40002443 PMC: 11852854. DOI: 10.3390/brainsci15020110.

Structure of transmembrane AMPA receptor regulatory protein subunit γ2.

Hale W, Romero A, Koylass N, Warrick C, Qiu Z, Huganir R Nat Commun. 2025; 16(1):671.

PMID: 39809794 PMC: 11733119. DOI: 10.1038/s41467-025-56027-1.

Molecular logic for cellular specializations that initiate the auditory parallel processing pathways.

Jing J, Hu M, Ngodup T, Ma Q, Lau S, Ljungberg M Nat Commun. 2025; 16(1):489.

PMID: 39788966 PMC: 11717940. DOI: 10.1038/s41467-024-55257-z.

MINFLUX fluorescence nanoscopy in biological tissue.

Moosmayer T, Kiszka K, Westphal V, Pape J, Leutenegger M, Steffens H Proc Natl Acad Sci U S A. 2024; 121(52):e2422020121.

PMID: 39705311 PMC: 11670107. DOI: 10.1073/pnas.2422020121.

The VGCC auxiliary subunit α2δ1 is an extracellular GluA1 interactor and regulates LTP, spatial memory, and seizure susceptibility.

Leana-Sandoval G, Kolli A, Sandoval M, Saavedra E, Li K, Chen L bioRxiv. 2024; .

PMID: 39677598 PMC: 11642997. DOI: 10.1101/2024.12.02.626379.

References

Dirnagl U, Iadecola C, Moskowitz M . Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999; 22(9):391-7. DOI: 10.1016/s0166-2236(99)01401-0. View

Liu S, Cull-Candy S . Synaptic activity at calcium-permeable AMPA receptors induces a switch in receptor subtype. Nature. 2000; 405(6785):454-8. DOI: 10.1038/35013064. View

Pickard L, Noel J, Henley J, Collingridge G, Molnar E . Developmental changes in synaptic AMPA and NMDA receptor distribution and AMPA receptor subunit composition in living hippocampal neurons. J Neurosci. 2000; 20(21):7922-31. PMC: 6772733. View

Chen L, Chetkovich D, Petralia R, Sweeney N, Kawasaki Y, Wenthold R . Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature. 2001; 408(6815):936-43. DOI: 10.1038/35050030. View

Schnell E, Sizemore M, Karimzadegan S, Chen L, Bredt D, Nicoll R . Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. Proc Natl Acad Sci U S A. 2002; 99(21):13902-7. PMC: 129795. DOI: 10.1073/pnas.172511199. View

Lee H, Takamiya K, Han J, Man H, Kim C, Rumbaugh G . Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell. 2003; 112(5):631-43. DOI: 10.1016/s0092-8674(03)00122-3. View

Francis P . Glutamatergic systems in Alzheimer's disease. Int J Geriatr Psychiatry. 2003; 18(Suppl 1):S15-21. DOI: 10.1002/gps.934. View

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

Turetsky D, Garringer E, Patneau D . Stargazin modulates native AMPA receptor functional properties by two distinct mechanisms. J Neurosci. 2005; 25(32):7438-48. PMC: 6725298. DOI: 10.1523/JNEUROSCI.1108-05.2005. View

10.

Hayashi T, Rumbaugh G, Huganir R . Differential regulation of AMPA receptor subunit trafficking by palmitoylation of two distinct sites. Neuron. 2005; 47(5):709-23. DOI: 10.1016/j.neuron.2005.06.035. View

11.

Alt A, Nisenbaum E, Bleakman D, Witkin J . A role for AMPA receptors in mood disorders. Biochem Pharmacol. 2006; 71(9):1273-88. DOI: 10.1016/j.bcp.2005.12.022. View

12.

Kawate T, Gouaux E . Fluorescence-detection size-exclusion chromatography for precrystallization screening of integral membrane proteins. Structure. 2006; 14(4):673-81. DOI: 10.1016/j.str.2006.01.013. View

13.

Sommer B, Keinanen K, Verdoorn T, Wisden W, Burnashev N, Herb A . Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS. Science. 1990; 249(4976):1580-5. DOI: 10.1126/science.1699275. View

14.

Sommer B, Kohler M, Sprengel R, Seeburg P . RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell. 1991; 67(1):11-9. DOI: 10.1016/0092-8674(91)90568-j. View

15.

Saglietti L, Dequidt C, Kamieniarz K, Rousset M, Valnegri P, Thoumine O . Extracellular interactions between GluR2 and N-cadherin in spine regulation. Neuron. 2007; 54(3):461-77. DOI: 10.1016/j.neuron.2007.04.012. View

16.

ONeill M, Witkin J . AMPA receptor potentiators: application for depression and Parkinson's disease. Curr Drug Targets. 2007; 8(5):603-20. DOI: 10.2174/138945007780618517. View

17.

Kessels H, Malinow R . Synaptic AMPA receptor plasticity and behavior. Neuron. 2009; 61(3):340-50. PMC: 3917551. DOI: 10.1016/j.neuron.2009.01.015. View

18.

Lu W, Shi Y, Jackson A, Bjorgan K, During M, Sprengel R . Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach. Neuron. 2009; 62(2):254-68. PMC: 3632349. DOI: 10.1016/j.neuron.2009.02.027. View

19.

Sobolevsky A, Rosconi M, Gouaux E . X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature. 2009; 462(7274):745-56. PMC: 2861655. DOI: 10.1038/nature08624. View

20.

Chen V, Arendall 3rd W, Headd J, Keedy D, Immormino R, Kapral G . MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 1):12-21. PMC: 2803126. DOI: 10.1107/S0907444909042073. View