Investigation of Cation Permeation Through AMPA Receptors by Molecular Dynamics Simulations

Abstract

AMPA Receptors (AMPAR) belong to the family of ionotropic glutamate receptors and are responsible for fast excitatory signal transduction at vertebrate synapses. They are crucial for all higher brain functions and defects in AMPARs can lead to severe neurodevelopmental disorders. We performed extensive molecular dynamics simulations (over 20 microseconds) of the transmembrane domain of a putative open AMPAR structure. These simulations revealed that the structure is indeed open and molecular dynamics (MD) are able to simulate ionic current through the ion channel structure derived from cryogenic electron microscopy. Permeation proceeded at physiological rates during the simulations, but depended on the force field used. We cross validated permeation rates of the monovalent cations potassium, sodium and caesium with single channel recordings. MD simulations of permeation of those ion types showed that the narrowest part with two glutamines in each subunit play the most important role in cation permeation. Rather than a single permissive structure, the selectivity filter of the ion channel is flexible, and allows different ions to permeate using distinct mechanisms but at similar rates.