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- EMDB-47521: GluA2-gamma2 complex bound glutamate and cyclothiazide -

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Basic information

Entry
Database: EMDB / ID: EMD-47521
TitleGluA2-gamma2 complex bound glutamate and cyclothiazide
Map dataFull map
Sample
  • Complex: GluA2-TARPgamma2 Complex bound to glutamate and cyclothiazide
    • Protein or peptide: Voltage-dependent calcium channel gamma-2 subunit
  • Protein or peptide: Isoform Flip of Glutamate receptor 2
  • Ligand: GLUTAMIC ACID
  • Ligand: CYCLOTHIAZIDE
Keywordsligand-gated ion channel / ionotropic glutamate receptor / ampa receptor / ion channel / TRANSPORT PROTEIN
Function / homology
Function and homology information


Presynaptic depolarization and calcium channel opening / LGI-ADAM interactions / Trafficking of AMPA receptors / eye blink reflex / positive regulation of protein localization to basolateral plasma membrane / cerebellar mossy fiber / postsynaptic neurotransmitter receptor diffusion trapping / regulation of AMPA receptor activity / membrane hyperpolarization / nervous system process ...Presynaptic depolarization and calcium channel opening / LGI-ADAM interactions / Trafficking of AMPA receptors / eye blink reflex / positive regulation of protein localization to basolateral plasma membrane / cerebellar mossy fiber / postsynaptic neurotransmitter receptor diffusion trapping / regulation of AMPA receptor activity / membrane hyperpolarization / nervous system process / protein targeting to membrane / voltage-gated calcium channel complex / spine synapse / neurotransmitter receptor localization to postsynaptic specialization membrane / dendritic spine neck / neuromuscular junction development / dendritic spine head / Activation of AMPA receptors / perisynaptic space / ligand-gated monoatomic cation channel activity / AMPA glutamate receptor activity / transmission of nerve impulse / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / kainate selective glutamate receptor activity / AMPA glutamate receptor complex / cellular response to glycine / extracellularly glutamate-gated ion channel activity / ionotropic glutamate receptor complex / immunoglobulin binding / asymmetric synapse / membrane depolarization / regulation of receptor recycling / glutamate receptor binding / Unblocking of NMDA receptors, glutamate binding and activation / positive regulation of synaptic transmission / regulation of postsynaptic membrane neurotransmitter receptor levels / voltage-gated calcium channel activity / response to fungicide / regulation of synaptic transmission, glutamatergic / glutamate-gated receptor activity / cytoskeletal protein binding / presynaptic active zone membrane / extracellular ligand-gated monoatomic ion channel activity / cellular response to brain-derived neurotrophic factor stimulus / glutamate-gated calcium ion channel activity / somatodendritic compartment / ionotropic glutamate receptor binding / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / ionotropic glutamate receptor signaling pathway / dendrite cytoplasm / SNARE binding / hippocampal mossy fiber to CA3 synapse / dendritic shaft / regulation of membrane potential / PDZ domain binding / synaptic transmission, glutamatergic / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / protein tetramerization / synaptic membrane / establishment of protein localization / postsynaptic density membrane / modulation of chemical synaptic transmission / cerebral cortex development / receptor internalization / Schaffer collateral - CA1 synapse / terminal bouton / response to calcium ion / synaptic vesicle membrane / synaptic vesicle / signaling receptor activity / presynapse / amyloid-beta binding / presynaptic membrane / growth cone / scaffold protein binding / chemical synaptic transmission / dendritic spine / perikaryon / postsynaptic membrane / neuron projection / postsynaptic density / axon / neuronal cell body / synapse / dendrite / protein-containing complex binding / protein kinase binding / glutamatergic synapse / cell surface / endoplasmic reticulum / protein-containing complex / identical protein binding / membrane / plasma membrane
Similarity search - Function
Voltage-dependent calcium channel, gamma-2 subunit / : / PMP-22/EMP/MP20/Claudin family / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel ...Voltage-dependent calcium channel, gamma-2 subunit / : / PMP-22/EMP/MP20/Claudin family / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / : / Ionotropic glutamate receptor / Eukaryotic homologues of bacterial periplasmic substrate binding proteins. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
Similarity search - Domain/homology
Voltage-dependent calcium channel gamma-2 subunit / Glutamate receptor 2
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsMontano Romero A / Carrillo E / Jayaraman V / Twomey EC
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM154904 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM122528 United States
Other privateKinship Foundation 22098168 United States
Other privateDiana Helis Henry Medical Research Foundation 142548 United States
CitationJournal: Nat Commun / Year: 2025
Title: Memantine inhibits calcium-permeable AMPA receptors.
Authors: Elisa Carrillo / Alejandra Montaño Romero / Cuauhtemoc U Gonzalez / Andreea L Turcu / Santiago Vázquez / Edward C Twomey / Vasanthi Jayaraman /
Abstract: Memantine is an US Food and Drug Administration (FDA) approved drug that is thought to selectively inhibit NMDA-subtype of ionotropic glutamate receptors (NMDARs). NMDARs enable calcium influx into ...Memantine is an US Food and Drug Administration (FDA) approved drug that is thought to selectively inhibit NMDA-subtype of ionotropic glutamate receptors (NMDARs). NMDARs enable calcium influx into neurons and are critical for normal brain function. However, increasing evidence shows that calcium influx in neurological diseases is augmented by calcium-permeable AMPA-subtype ionotropic glutamate receptors (AMPARs). Here, we demonstrate that these calcium-permeable AMPARs (CP-AMPARs) are inhibited by memantine. Electrophysiology unveils that memantine inhibition of CP-AMPARs is dependent on their calcium permeability and the presence of their neuronal auxiliary subunit transmembrane AMPAR regulatory proteins (TARPs). Through cryo-electron microscopy we elucidate that memantine blocks CP-AMPAR ion channels in a unique mechanism of action from NMDARs. Furthermore, we demonstrate that memantine inhibits a gain of function AMPAR mutation found in a patient with a neurodevelopmental disorder. Our findings unlock potential exploitation of this site to design more specific drugs targeting CP-AMPARs.
History
DepositionOct 25, 2024-
Header (metadata) releaseJun 18, 2025-
Map releaseJun 18, 2025-
UpdateJul 16, 2025-
Current statusJul 16, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47521.png

Downloads & links

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Map

FileDownload / File: emd_47521.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull map
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 480 pix.
= 446.4 Å		0.93 Å/pix.
x 480 pix.
= 446.4 Å		0.93 Å/pix.
x 480 pix.
= 446.4 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.70032513 - 0.9767046
Average (Standard dev.)0.0007664605 (±0.011811426)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 446.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: TMD local map

Fileemd_47521_additional_1.map
AnnotationTMD local map
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Additional map: TMD local half map 1

Fileemd_47521_additional_2.map
AnnotationTMD local half map 1
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Additional map: TMD local half map 2

Fileemd_47521_additional_3.map
AnnotationTMD local half map 2
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Histogram

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Half map: half map 1

Fileemd_47521_half_map_1.map
Annotationhalf map 1
Projections & Slices
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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: half map 2

Fileemd_47521_half_map_2.map
Annotationhalf map 2
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Sample components

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Entire : GluA2-TARPgamma2 Complex bound to glutamate and cyclothiazide

EntireName: GluA2-TARPgamma2 Complex bound to glutamate and cyclothiazide
Components
  • Complex: GluA2-TARPgamma2 Complex bound to glutamate and cyclothiazide
    • Protein or peptide: Voltage-dependent calcium channel gamma-2 subunit
  • Protein or peptide: Isoform Flip of Glutamate receptor 2
  • Ligand: GLUTAMIC ACID
  • Ligand: CYCLOTHIAZIDE

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Supramolecule #1: GluA2-TARPgamma2 Complex bound to glutamate and cyclothiazide

SupramoleculeName: GluA2-TARPgamma2 Complex bound to glutamate and cyclothiazide
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2
Source (natural)Organism: Rattus norvegicus (Norway rat)

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Macromolecule #1: Isoform Flip of Glutamate receptor 2

MacromoleculeName: Isoform Flip of Glutamate receptor 2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 90.967711 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: NSIQIGGLFP RGADQEYSAF RVGMVQFSTS EFRLTPHIDN LEVANSFAVT NAFCSQFSRG VYAIFGFYDK KSVNTITSFC GTLHVSFIT PSFPTDGTHP FVIQMRPDLK GALLSLIEYY QWDKFAYLYD SDRGLSTLQA VLDSAAEKKW QVTAINVGNI N NDKKDETY ...String:
NSIQIGGLFP RGADQEYSAF RVGMVQFSTS EFRLTPHIDN LEVANSFAVT NAFCSQFSRG VYAIFGFYDK KSVNTITSFC GTLHVSFIT PSFPTDGTHP FVIQMRPDLK GALLSLIEYY QWDKFAYLYD SDRGLSTLQA VLDSAAEKKW QVTAINVGNI N NDKKDETY RSLFQDLELK KERRVILDCE RDKVNDIVDQ VITIGKHVKG YHYIIANLGF TDGDLLKIQF GGAEVSGFQI VD YDDSLVS KFIERWSTLE EKEYPGAHTA TIKYTSALTY DAVQVMTEAF RNLRKQRIEI SRRGNAGDCL ANPAVPWGQG VEI ERALKQ VQVEGLSGNI KFDQNGKRIN YTINIMELKT NGPRKIGYWS EVDKMVLTED DTSGLEQKTV VVTTILESPY VMMK KNHEM LEGNERYEGY CVDLAAEIAK HCGFKYKLTI VGDGKYGARD ADTKIWNGMV GELVYGKADI AIAPLTITLV REEVI DFSK PFMSLGISIM IKKPQKSKPG VFSFLDPLAY EIWMCIVFAY IGVSVVLFLV SRFSPYEWHT EEFEDGRETQ SSESTN EFG IFNSLWFSLG AFMQQGCDIS PRSLSGRIVG GVWWFFTLII ISSYTANLAA FLTVERMVSP IESAEDLSKQ TEIAYGT LD SGSTKEFFRR SKIAVFDKMW TYMRSAEPSV FVRTTAEGVA RVRKSKGKYA YLLESTMNEY IEQRKPCDTM KVGGNLDS K GYGIATPKGS SLGTPVNLAV LKLSEQGVLD KLKNKWWYDK GECGAKDSGS KEKTSALSLS NVAGVFYILV GGLGLAMLV ALIEFCYKSR A

UniProtKB: Glutamate receptor 2

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Macromolecule #2: Voltage-dependent calcium channel gamma-2 subunit

MacromoleculeName: Voltage-dependent calcium channel gamma-2 subunit / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.008461 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LFDRGVQMLL TTVGAFAAFS LMTIAVGTDY WLYSRGVCKT KSVSENETSK KNEEVMTHSG LWRTCCLEGN FKGLCKQIDH FPEDADYEA DTAEYFLRAV RASSIFPILS VILLFMGGLC IAASEFYKTR HNIILSAGIF FVSAGLSNII GIIVYISANA G DPSKSDSK ...String:
LFDRGVQMLL TTVGAFAAFS LMTIAVGTDY WLYSRGVCKT KSVSENETSK KNEEVMTHSG LWRTCCLEGN FKGLCKQIDH FPEDADYEA DTAEYFLRAV RASSIFPILS VILLFMGGLC IAASEFYKTR HNIILSAGIF FVSAGLSNII GIIVYISANA G DPSKSDSK KNSYSYGWSF YFGALSFIIA EMVGVLAVHM FIDRHKQLTG

UniProtKB: Voltage-dependent calcium channel gamma-2 subunit

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Macromolecule #3: GLUTAMIC ACID

MacromoleculeName: GLUTAMIC ACID / type: ligand / ID: 3 / Number of copies: 4 / Formula: GLU
Molecular weightTheoretical: 147.129 Da
Chemical component information

ChemComp-GLU:
GLUTAMIC ACID

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Macromolecule #4: CYCLOTHIAZIDE

MacromoleculeName: CYCLOTHIAZIDE / type: ligand / ID: 4 / Number of copies: 4 / Formula: CYZ
Molecular weightTheoretical: 389.878 Da
Chemical component information

ChemComp-CYZ:
CYCLOTHIAZIDE

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration4 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: ab initio
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 87724
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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