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

• DOI: 10.1016/j.molcel.2021.09.030
• Publication Date: 2021-10-22T03:55:16Z
• Authors: Oleg Klykov; Shanti Pal Gangwar; Maria V. Yelshans...; Laura Yen; Alexander I. Sobo...
• Keywords: 0301 basic medicine; 0303 health sciences; Patch-Clamp Techniques; Polymers; Protein Conformation; Amino Acid Motifs; Cryoelectron Microscopy; Lipid Bilayers; Molecular Conformation; Membrane Proteins; Synaptic Transmission; Rats; 03 medical and health sciences; HEK293 Cells; Protein Domains; Claudins; Image Processing, Computer-Assisted; Animals; Humans; Calcium Channels; Receptors, AMPA; Dimerization; Protein Binding

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.