Cannabidiol inhibits febrile seizure by modulating AMPA receptor kinetics through its interaction with the N-terminal domain of GluA1/GluA2

At synapses throughout the mammalian brain, AMPA receptors form complexes with auxiliary proteins, including TARPs. However, how TARPs modulate AMPA receptor gating remains poorly understood. We built structural models of TARP-AMPA receptor complexes for TARPs γ2 and γ8, combining recent structural studies and de novo structure predictions. These models, combined with peptide binding assays, provide evidence for multiple interactions between GluA2 and variable extracellular loops of TARPs. Substitutions and deletions of these loops had surprisingly rich effects on the kinetics of glutamate-activated currents, without any effect on assembly. Critically, by altering the two interacting loops of γ2 and γ8, we could entirely remove all allosteric modulation of GluA2, without affecting formation of AMPA receptor-TARP complexes. Likewise, substitutions in the linker domains of GluA2 completely removed any effect of γ2 on receptor kinetics, indicating a dominant role for this previously overlooked site proximal to the AMPA receptor channel gate.

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Long-term potentiation is independent of the C-tail of the GluA1 AMPA receptor subunit

eLife ◽

10.7554/elife.58042 ◽

2020 ◽

Vol 9 ◽

Author(s):

Javier Díaz-Alonso ◽

Wade Morishita ◽

Salvatore Incontro ◽

Jeffrey Simms ◽

Julia Holtzman ◽

...

Keyword(s):

Spatial Memory ◽

Morris Water Maze ◽

Ampa Receptor ◽

Water Maze ◽

Long Term Potentiation ◽

Receptor Subunit ◽

Terminal Domain ◽

Term Potentiation ◽

Ampa Receptor Subunit

We tested the proposal that the C-terminal domain (CTD) of the AMPAR subunit GluA1 is required for LTP. We found that a knock-in mouse lacking the CTD of GluA1 expresses normal LTP and spatial memory, assayed by the Morris water maze. Our results support a model in which LTP generates synaptic slots, which capture passively diffusing AMPARs.

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The N-terminal Domain Modulates α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor Desensitization

Journal of Biological Chemistry ◽

10.1074/jbc.m113.526301 ◽

2014 ◽

Vol 289 (19) ◽

pp. 13197-13205 ◽

Cited By ~ 17

Author(s):

Tommi Möykkynen ◽

Sarah K. Coleman ◽

Artur Semenov ◽

Kari Keinänen

Keyword(s):

Ampa Receptor ◽

Receptor Desensitization ◽

Terminal Domain

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The Relationship between Agonist Potency and AMPA Receptor Kinetics

Biophysical Journal ◽

10.1529/biophysj.106.084426 ◽

2006 ◽

Vol 91 (4) ◽

pp. 1336-1346 ◽

Cited By ~ 37

Author(s):

Wei Zhang ◽

Antoine Robert ◽

Stine B. Vogensen ◽

James R. Howe

Keyword(s):

Ampa Receptor ◽

Receptor Kinetics ◽

The Relationship

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Surface Expression of GluR-D AMPA Receptor Is Dependent on an Interaction between Its C-Terminal Domain and a 4.1 Protein

Journal of Neuroscience ◽

10.1523/jneurosci.23-03-00798.2003 ◽

2003 ◽

Vol 23 (3) ◽

pp. 798-806 ◽

Cited By ~ 67

Author(s):

Sarah K. Coleman ◽

Chunlin Cai ◽

David G. Mottershead ◽

Jukka-Pekka Haapalahti ◽

Kari Keinänen

Keyword(s):

Ampa Receptor ◽

Surface Expression ◽

Terminal Domain

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Control of AMPA receptor activity by the extracellular loops of auxiliary proteins

10.1101/140053 ◽

2017 ◽

Author(s):

Irene Riva ◽

Clarissa Eibl ◽

Rudolf Volkmer ◽

Anna L. Carbone ◽

Andrew J. R. Plested

Keyword(s):

Ampa Receptor ◽

Ampa Receptors ◽

De Novo ◽

Dominant Role ◽

Mammalian Brain ◽

Binding Assays ◽

Receptor Kinetics ◽

Receptor Complexes ◽

Extracellular Loops ◽

Kinetics Of

AbstractAt synapses throughout the mammalian brain, AMPA receptors form complexes with auxiliary proteins, including TARPs. However, how TARPs modulate AMPA receptor gating remains poorly understood. We built structural models of TARP-AMPA receptor complexes for TARPs γ2 and γ8, combining recent structural studies and de novo structure predictions. These models, combined with peptide binding assays, provide evidence for multiple interactions between GluA2 and variable extracellular loops of TARPs. Substitutions and deletions of these loops had surprisingly rich effects on the kinetics of glutamate-activated currents, without any effect on assembly. Critically, by altering the two interacting loops of γ2 and γ8, we could entirely remove all allosteric modulation of GluA2, without affecting formation of AMPA receptor-TARP complexes. Likewise, substitutions in the linker domains of GluA2 completely removed any effect of Y2 on receptor kinetics, indicating a dominant role for this previously overlooked site proximal to the AMPA receptor channel gate.

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