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Binding of a negative allosteric modulator and competitive antagonist can occur simultaneously at the ionotropic glutamate receptor GluA2

Krintel, Christian LU ; Dorosz, Jerzy ; Larsen, Andreas Haahr ; Seneca Thorsen, Thor ; Venskutonytė, Raminta LU ; Mirza, Osman ; Gajhede, Michael ; Boesen, Thomas and Kastrup, Jette Sandholm Jensen (2020) In The FEBS Journal
Abstract

Ionotropic glutamate receptors are ligand-gated ion channels governing neurotransmission in the central nervous system. Three major types of antagonists are known for the AMPA-type receptor GluA2: competitive, non-competitive (i.e. negative allosteric modulators; NAMs) used for treatment of epilepsy, and uncompetitive antagonists. We here report a 4.65 Å resolution X-ray structure of GluA2, revealing that four molecules of the competitive antagonist ZK200775 and four molecules of the NAM GYKI53655 are capable of binding at the same time. Using negative stain electron microscopy, we show that GYKI53655 alone or ZK200775/GYKI53655 in combination predominantly result in compact receptor forms. The agonist AMPA provides a mixed population... (More)

Ionotropic glutamate receptors are ligand-gated ion channels governing neurotransmission in the central nervous system. Three major types of antagonists are known for the AMPA-type receptor GluA2: competitive, non-competitive (i.e. negative allosteric modulators; NAMs) used for treatment of epilepsy, and uncompetitive antagonists. We here report a 4.65 Å resolution X-ray structure of GluA2, revealing that four molecules of the competitive antagonist ZK200775 and four molecules of the NAM GYKI53655 are capable of binding at the same time. Using negative stain electron microscopy, we show that GYKI53655 alone or ZK200775/GYKI53655 in combination predominantly result in compact receptor forms. The agonist AMPA provides a mixed population of compact and bulgy shapes of GluA2 not impacted by addition of GYKI53655. Taken together, this suggests that the two different mechanisms of antagonism that lead to channel closure are independent and that the distribution between bulgy and compact receptors primarily depends on the ligand bound in the glutamate binding site.

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Contribution to journal
publication status
epub
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in
The FEBS Journal
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • pmid:32543078
  • scopus:85087694502
ISSN
1742-464X
DOI
10.1111/febs.15455
language
English
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yes
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This article is protected by copyright. All rights reserved.
id
1ec1b6f8-6d54-47e4-8746-413759c7464a
date added to LUP
2020-06-21 17:06:40
date last changed
2020-07-29 06:15:41
@article{1ec1b6f8-6d54-47e4-8746-413759c7464a,
  abstract     = {<p>Ionotropic glutamate receptors are ligand-gated ion channels governing neurotransmission in the central nervous system. Three major types of antagonists are known for the AMPA-type receptor GluA2: competitive, non-competitive (i.e. negative allosteric modulators; NAMs) used for treatment of epilepsy, and uncompetitive antagonists. We here report a 4.65 Å resolution X-ray structure of GluA2, revealing that four molecules of the competitive antagonist ZK200775 and four molecules of the NAM GYKI53655 are capable of binding at the same time. Using negative stain electron microscopy, we show that GYKI53655 alone or ZK200775/GYKI53655 in combination predominantly result in compact receptor forms. The agonist AMPA provides a mixed population of compact and bulgy shapes of GluA2 not impacted by addition of GYKI53655. Taken together, this suggests that the two different mechanisms of antagonism that lead to channel closure are independent and that the distribution between bulgy and compact receptors primarily depends on the ligand bound in the glutamate binding site.</p>},
  author       = {Krintel, Christian and Dorosz, Jerzy and Larsen, Andreas Haahr and Seneca Thorsen, Thor and Venskutonytė, Raminta and Mirza, Osman and Gajhede, Michael and Boesen, Thomas and Kastrup, Jette Sandholm Jensen},
  issn         = {1742-464X},
  language     = {eng},
  month        = {06},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {The FEBS Journal},
  title        = {Binding of a negative allosteric modulator and competitive antagonist can occur simultaneously at the ionotropic glutamate receptor GluA2},
  url          = {http://dx.doi.org/10.1111/febs.15455},
  doi          = {10.1111/febs.15455},
  year         = {2020},
}