Structure and desensitization of AMPA receptor complexes with type II TARP γ5 and GSG1L

Mol Cell. 2021 Dec 2;81(23):4771-4783.e7. doi: 10.1016/j.molcel.2021.09.030. Epub 2021 Oct 21.

Abstract

AMPA receptors (AMPARs) mediate the majority of excitatory neurotransmission. Their surface expression, trafficking, gating, and pharmacology are regulated by auxiliary subunits. Of the two types of TARP auxiliary subunits, type I TARPs assume activating roles, while type II TARPs serve suppressive functions. We present cryo-EM structures of GluA2 AMPAR in complex with type II TARP γ5, which reduces steady-state currents, increases single-channel conductance, and slows recovery from desensitization. Regulation of AMPAR function depends on its ligand-binding domain (LBD) interaction with the γ5 head domain. GluA2-γ5 complex shows maximum stoichiometry of two TARPs per AMPAR tetramer, being different from type I TARPs but reminiscent of the auxiliary subunit GSG1L. Desensitization of both GluA2-GSG1L and GluA2-γ5 complexes is accompanied by rupture of LBD dimer interface, while GluA2-γ5 but not GluA2-GSG1L LBD dimers remain two-fold symmetric. Different structural architectures and desensitization mechanisms of complexes with auxiliary subunits endow AMPARs with broad functional capabilities.

Keywords: AMPA receptor; GSG1L; TARP; cryo-EM; current kinetics; desensitization; gating; iGluR; symmetry; γ5.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Calcium Channels / chemistry*
  • Claudins / chemistry*
  • Cryoelectron Microscopy
  • Dimerization
  • HEK293 Cells
  • Humans
  • Image Processing, Computer-Assisted
  • Lipid Bilayers / chemistry
  • Membrane Proteins
  • Molecular Conformation
  • Patch-Clamp Techniques
  • Polymers
  • Protein Binding
  • Protein Conformation
  • Protein Domains
  • Rats
  • Receptors, AMPA / chemistry*
  • Synaptic Transmission

Substances

  • CACNG5 protein, human
  • Cacng5 protein, rat
  • Calcium Channels
  • Claudins
  • GSG1L protein, human
  • GSG1L protein, rat
  • Lipid Bilayers
  • Membrane Proteins
  • Polymers
  • Receptors, AMPA
  • glutamate receptor ionotropic, AMPA 2