Conformational Flexibility of the Ligand-Binding Domain Dimer in Kainate Receptor Gating and Desensitization

Nayeem, Naushaba; Mayans, Olga; Green, Tim

Conformational Flexibility of the Ligand-Binding Domain Dimer in Kainate Receptor Gating and Desensitization

Dateien

Nayeem_0-406434.pdf(726.96 KB)

Datum

2011

Autor:innen

Nayeem, Naushaba

Mayans, Olga

Green, Tim

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

Journal of Neuroscience ; 31 (2011), 8. - S. 2916-2924. - ISSN 0270-6474. - eISSN 1529-2401

Zusammenfassung

AMPA- and kainate (KA)-selective ionotropic glutamate receptors (iGluRs) respond to agonist by opening (gating), then closing (desensitizing) in quick succession. Gating has been linked to agonist-induced changes within the ligand-binding domain (LBD), and desensitization to rearrangement of a dimer formed by neighboring LBDs. To explore the role of dimer conformation in both gating and desensitization, we compared the conformational effects of two kainate receptor mutants. The first, GluK2-D776K, blocks desensitization of macroscopic current responses ("macroscopic desensitization"). The second, GluK2-M770K, accelerates macroscopic desensitization and eliminates the effects of external ions on channel kinetics. Using structures determined by x-ray crystallography, we found that in both mutants the introduced lysines act as tethered cations, displacing sodium ions from their binding sites within the dimer interface. This results in new inter- and intra-protomer contacts in D776K and M770K respectively, explaining the effects of these mutations on dimer stability and desensitization kinetics. Further, chloride binding was unaffected by the M770K mutation, even though binding of sodium ions has been proposed to promote dimer stability by stabilizing anion binding. This suggests sodium binding may affect receptor function more directly than currently supposed. Notably, we also observed a ligand-specific shift in dimer conformation when comparing LBD dimers in complex with glutamate or the partial agonist KA, revealing a previously unidentified role for dimer orientation in iGluR gating.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Zitieren

ISO 690

NAYEEM, Naushaba, Olga MAYANS, Tim GREEN, 2011. Conformational Flexibility of the Ligand-Binding Domain Dimer in Kainate Receptor Gating and Desensitization. In: Journal of Neuroscience. 31(8), pp. 2916-2924. ISSN 0270-6474. eISSN 1529-2401. Available under: doi: 10.1523/JNEUROSCI.4771-10.2011

BibTex

@article{Nayeem2011-02-23Confo-38682,
  year={2011},
  doi={10.1523/JNEUROSCI.4771-10.2011},
  title={Conformational Flexibility of the Ligand-Binding Domain Dimer in Kainate Receptor Gating and Desensitization},
  number={8},
  volume={31},
  issn={0270-6474},
  journal={Journal of Neuroscience},
  pages={2916--2924},
  author={Nayeem, Naushaba and Mayans, Olga and Green, Tim}
}

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    <dcterms:abstract xml:lang="eng">AMPA- and kainate (KA)-selective ionotropic glutamate receptors (iGluRs) respond to agonist by opening (gating), then closing (desensitizing) in quick succession. Gating has been linked to agonist-induced changes within the ligand-binding domain (LBD), and desensitization to rearrangement of a dimer formed by neighboring LBDs. To explore the role of dimer conformation in both gating and desensitization, we compared the conformational effects of two kainate receptor mutants. The first, GluK2-D776K, blocks desensitization of macroscopic current responses ("macroscopic desensitization"). The second, GluK2-M770K, accelerates macroscopic desensitization and eliminates the effects of external ions on channel kinetics. Using structures determined by x-ray crystallography, we found that in both mutants the introduced lysines act as tethered cations, displacing sodium ions from their binding sites within the dimer interface. This results in new inter- and intra-protomer contacts in D776K and M770K respectively, explaining the effects of these mutations on dimer stability and desensitization kinetics. Further, chloride binding was unaffected by the M770K mutation, even though binding of sodium ions has been proposed to promote dimer stability by stabilizing anion binding. This suggests sodium binding may affect receptor function more directly than currently supposed. Notably, we also observed a ligand-specific shift in dimer conformation when comparing LBD dimers in complex with glutamate or the partial agonist KA, revealing a previously unidentified role for dimer orientation in iGluR gating.</dcterms:abstract>
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