Zinc Potentiates GluK3 Glutamate Receptor Function by Stabilizing the Ligand Binding Domain Dimer Interface

CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France.
Neuron (Impact Factor: 15.05). 11/2012; 76(3):565-78. DOI: 10.1016/j.neuron.2012.08.027
Source: PubMed


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.

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Available from: David Perrais, Sep 11, 2015
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    • "on is consistent with luminescence resonance energy transfer measurements in AMPA ( Gonzalez et al . 2010 ) and NMDA receptors ( Rambhadran et al . 2010 ) . In KA receptors , the stability of the LBD dimer interface depends on the occupancy of the ion binding sites it harbours ( Plested & Mayer , 2007 ; Plested et al . 2008 ; Nayeem et al . 2009 ; Veran et al . 2012 ; Dawe et al . 2013 ) . A complete rupture of the intradimer interface and separation of LBDs during desensitization was proposed for GluK2 KA receptors ( Schauder et al . 2013 ) . On the other hand , GluN1 – GluN2A NMDA receptors with the crosslinked upper D1 lobes had intact desensitization but their activation was deeply impaired : t"
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