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 y5, 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 y5 head domain. GluA2-y5 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-y5 complexes is accompanied by rupture of LBD dimer interface, while GluA2-y5 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.

Automated summary

AMPARs mediate the majority of excitatory neurotransmission and their function is regulated by auxiliary subunits. Different types of TARP auxiliary subunits have different roles, and the structural and mechanistic variations of complexes with auxiliary subunits endow AMPARs with broad functional capabilities.