GluA2-containing AMPA receptors form a continuum of Ca-permeable channels.

Fast excitatory neurotransmission in the mammalian brain is mediated by cation-selective AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors (AMPARs). AMPARs are critical for the learning and memory mechanisms of Hebbian plasticity and glutamatergic synapse homeostasis, with recent work establishing that AMPAR missense mutations can cause autism and intellectual disability. AMPARs have been grouped into two functionally distinct tetrameric assemblies based on the inclusion or exclusion of the GluA2 subunit that determines Ca permeability through RNA editing. GluA2-containing AMPARs are the most abundant in the central nervous system and considered to be Ca impermeable. Here we show this is not the case. Contrary to conventional understanding, GluA2-containing AMPARs form a continuum of polyamine-insensitive ion channels with varying degrees of Ca permeability. Their ability to transport Ca is shaped by the subunit composition of AMPAR tetramers as well as the spatial orientation of transmembrane AMPAR regulatory proteins and cornichon auxiliary subunits. Ca crosses the ion-conduction pathway by docking to an extracellular binding site that helps funnel divalent ions into the pore selectivity filter. The dynamic range in Ca permeability, however, arises because auxiliary subunits primarily modify the selectivity filter. Taken together, our work proposes a broader role for AMPARs in Ca signalling in the mammalian brain and offers mechanistic insight into the pathogenic nature of missense mutations.