<p>Fast excitatory neurotransmission in the mammalian brain is mediated by cation-selective AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors (AMPARs)^{<CitationRef CitationID="CR1">1</CitationRef>}. AMPARs are critical for the learning and memory mechanisms of Hebbian plasticity^{<CitationRef CitationID="CR2">2</CitationRef>} and glutamatergic synapse homeostasis^{<CitationRef CitationID="CR3">3</CitationRef>}, with recent work establishing that AMPAR missense mutations can cause autism and intellectual disability^{<CitationRef AdditionalCitationIDS="CR5 CR6" CitationID="CR4">4</CitationRef>–<CitationRef CitationID="CR7">7</CitationRef>}. 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 editing^{<CitationRef CitationID="CR8">8</CitationRef>,<CitationRef CitationID="CR9">9</CitationRef>}. GluA2-containing AMPARs are the most abundant in the central nervous system and considered to be Ca²⁺ impermeable^{<CitationRef CitationID="CR10">10</CitationRef>}. 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.</p>