GluA2-containing AMPA receptors form a continuum of Ca2+-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)1. AMPARs are critical for the learning and memory mechanisms of Hebbian plasticity2 and glutamatergic synapse homeostasis3, with recent work establishing that AMPAR missense mutations can cause autism and intellectual disability4–7. AMPARs have been grouped into two functionally distinct tetrameric assemblies based on the inclusion or exclusion of the GluA2 subunit that determines Ca2+ permeability through RNA editing8,9. GluA2-containing AMPARs are the most abundant in the central nervous system and considered to be Ca2+ impermeable10. 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 Ca2+ permeability. Their ability to transport Ca2+ is shaped by the subunit composition of AMPAR tetramers as well as the spatial orientation of transmembrane AMPAR regulatory proteins and cornichon auxiliary subunits. Ca2+ 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 Ca2+ permeability, however, arises because auxiliary subunits primarily modify the selectivity filter. Taken together, our work proposes a broader role for AMPARs in Ca2+ signalling in the mammalian brain and offers mechanistic insight into the pathogenic nature of missense mutations.