Structure and mechanism of glutamate receptor ion channel assembly, activation and modulation

Ionotropic glutamate receptors (iGluRs) are ligand gated ion channels that mediate excitatory synaptic transmission in the brain of vertebrates. A rapidly growing body of crystal structures for isolated iGluR extracellular domains, and more recently a full length AMPA receptor, combined with data from electrophysiological experiments and MD simulations, provides a framework that makes it possible to investigate the molecular basis for assembly, gating and modulation. These unprecedented advances in structural biology are constantly challenged by novel functional properties that emerge despite decades of functional analysis, and by a growing family of auxiliary proteins that modulate iGluR activity and assembly.

Graphical abstractDownload high-res image (213KB)Download full-size imageResearch highlights► Analysis of glutamate receptor structure is becoming increasingly sophisticated. ► Novel features include symmetry mismatch and a dimer of dimers assembly. ► Dimer formation is a key mechanism in AMPA receptor biogenesis. ► In NMDA receptors the amino terminal domain acts as an endogenous regulator. ► NMR data and molecular dynamics simulations give insights into receptor energetics. ► Auxiliary subunits are now key targets for structural and mechanistic analysis.