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

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. [Display omitted] •Desensitized and closed-state structures of GluA2 with type II TARP γ5 and GSG1L•γ5 and GSG1L head domains define 2:1 stoichiometry of their complexes with GluA2•LBD dimer interface ruptures during GluA2-γ5 and GluA2-GSG1L desensitization•Desensitized LBD dimers remain two-fold symmetric in GluA2-γ5 but not in GluA2-GSG1L Klykov et al. solve structures of AMPA receptor in complex with auxiliary subunits type II TARP γ5 and GSG1L in closed and desensitized states, with stoichiometry of two auxiliary subunits per receptor tetramer. GluA2-γ5 and GluA2-GSG1L desensitization is accompanied by rupture of LBD dimer interface but follows different structural mechanisms.