title: Zinc potentiates GluK3 glutamate receptor function by stabilizing the ligand binding domain dimer interface.
abstract: Kainate receptors (KARs) play a key role in the regulation of synaptic networks. Here, we show that zinc, a cation released at a subset of glutamatergic synapses, potentiates glutamate currents mediated by homomeric and heteromeric KARs containing GluK3 at 10-100 μM concentrations, whereas it inhibits other KAR subtypes. Potentiation of GluK3 currents is mainly due to reduced desensitization, as shown by kinetic analysis and desensitization mutants. Crystallographic and mutation analyses revealed that a specific zinc binding site is formed at the base of the ligand binding domain (LBD) dimer interface by a GluK3-specific aspartate (Asp759), together with two conserved residues, His762 and Asp730, the latter located on the partner subunit. In addition, we propose that tetrameric GluK2/GluK3 receptors are likely assembled as pairs of heterodimeric LBDs. Therefore, zinc binding stabilizes the labile GluK3 dimer interface, slows desensitization, and potentiates currents, providing a mechanism for KAR potentiation at glutamatergic synapses.
authors.affiliation: University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Veran
authors.forename: Janesh
authors.initials: J
authors.lastname: Kumar
authors.forename: Paulo S
authors.initials: PS
authors.lastname: Pinheiro
authors.forename: Axel
authors.initials: A
authors.lastname: Athané
authors.forename: Mark L
authors.initials: ML
authors.lastname: Mayer
authors.forename: David
authors.initials: D
authors.lastname: Perrais
authors.forename: Christophe
authors.initials: C
authors.lastname: Mulle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D018360:Crystallography, X-Ray / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D055503:Protein Multimerization / Q000502:physiology*; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D018092:Kainic Acid Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015032:Zinc / Q000502:physiology*; D000097808:GluK3 Kainate Receptor
chemical_list: D008024:Ligands; D018092:Kainic Acid Receptors; D015032:Zinc; D000097808:GluK3 Kainate Receptor