From Assembly to Activation: Structural Mechanisms Governing AMPA Glutamate Receptor Function

  
AMPA-type glutamate receptors (AMPARs) are ion channels that mediate fast
excitatory neurotransmission in the central nervous system. They are also
involved in synaptic plasticity and memory formation, and their dysfunction is
associated with neurodegenerative disorders and epilepsy. Four protein subunits,
GluA1 to GluA4, assemble to form a tetrameric ion channel core with variable
stoichiometries, resulting in distinct ion permeability and gating kinetics. Auxiliary
proteins, including TARPs and cornichons, further increase the functional
diversity of native AMPAR complexes across brain regions and developmental
stages.Our group focuses on understanding this diversity by identifying how
different subunit compositions give rise to unique receptor architectures and
dynamics.
Here, I will present our recent structural work on GluA2-lacking AMPARs, with a
particular focus on GluA4 receptors, which are predominant in the cerebellum
and during early development. We combine cryo-EM analysis and
electrophysiology to investigate the molecular architecture and gating cycle of
GluA4 AMPARs, both in isolation and in complex with the auxiliary protein TARP-
γ2. Our data reveal changes in quaternary organization that underlie the fastgating
properties of GluA4. I will also compare these findings with our previous
structures of GluA3 and GluA2-containing heteromers, providing an integrated
overview of structural gating mechanisms that expand glutamatergic signaling in
the mammalian brain.