Structural and Functional Insights into GluK3-kainate Receptor Desensitization and Recovery

Sci Rep. 2019 Jul 16;9(1):10254. doi: 10.1038/s41598-019-46770-z.

Abstract

GluK3-kainate receptors are atypical members of the iGluR family that reside at both the pre- and postsynapse and play a vital role in the regulation of synaptic transmission. For a better understanding of structural changes that underlie receptor functions, GluK3 receptors were trapped in desensitized and resting/closed states and structures analyzed using single particle cryo-electron microscopy. While the desensitized GluK3 has domain organization as seen earlier for another kainate receptor-GluK2, antagonist bound GluK3 trapped a resting state with only two LBD domains in dimeric arrangement necessary for receptor activation. Using structures as a guide, we show that the N-linked glycans at the interface of GluK3 ATD and LBD likely mediate inter-domain interactions and attune receptor-gating properties. The mutational analysis also identified putative N-glycan interacting residues. Our results provide a molecular framework for understanding gating properties unique to GluK3 and exploring the role of N-linked glycosylation in their modulation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Alanine / analogs & derivatives
  • Alanine / chemistry
  • Alanine / metabolism
  • Animals
  • Binding Sites
  • Cryoelectron Microscopy
  • Crystallography, X-Ray
  • HEK293 Cells
  • Humans
  • Mutagenesis, Site-Directed
  • Polysaccharides / chemistry
  • Polysaccharides / metabolism
  • Protein Conformation
  • Rats
  • Receptors, Kainic Acid / agonists
  • Receptors, Kainic Acid / chemistry*
  • Receptors, Kainic Acid / genetics
  • Receptors, Kainic Acid / metabolism*
  • Thymine / analogs & derivatives
  • Thymine / chemistry
  • Thymine / metabolism

Substances

  • GluK3 kainate receptor
  • Polysaccharides
  • Receptors, Kainic Acid
  • UBP 310
  • Alanine
  • Thymine