Mechanisms of Ion Permeation in the AMPA Receptor Ion Channel

Excitatory synaptic transmission in the human nervous system is mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), tetrameric ligand-gated ion channels localized in the excitatory post-synaptic membrane. AMPARs are activated by the binding of the neurotransmitter glutamate (Glu), which opens the ion channel and allows the influx of Na⁺ and Ca²⁺ ions into the post-synaptic neuron, initiating signal transduction. Despite many efforts, a bona fide ion permeation pathway of both monovalent and divalent cations in AMPARs remains elusive. From analyzing our cryo-electron microscopy (cryo-EM) map of an open calcium-permeable AMPAR (CP-AMPAR) ion channel, we identified potential sites vital to permeation of cations through the channel. To delineate mechanisms of permeation, we studied the channel with all-atom molecular dynamics (MD) simulations. Both Na⁺ and Ca²⁺ ions are coordinated by an entry site at the top of the channel prior to entering the selectivity filter. A mutation at the filter (Q607E), implicated in a neurodevelopmental disorder, makes the channel more susceptible to Zn²⁺ block but also creates a more energetically favorable environment for Na⁺ and Ca²⁺ permeation through the ion channel. These findings describe a biophysical basis for ion permeation in CP-AMPARs and how disease mutations alter the channel, which will inform therapeutic design against disease mutations in AMPARs that alter the ion channel.