Ion permeation in ionotropic glutamate receptors: Still dynamic after all these years

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the vast majority of fast synaptic transmission in the nervous system. When the iGluR ion channel is in the open or conducting conformation, it is non-selective for monovalent cations, driving membrane excitation. Often the channel is also permeable to Ca²⁺. This process of Ca²⁺ permeation and its physiological and pathological consequences depend strongly on the specific iGluR subtype as well as the specific subunits in the oligomeric complex. Recent evidence has highlighted additional levels of diversity to this process including a dependence on specific auxiliary subunits in non-NMDARs and post-translational modifications in NMDARs. Various de novo missense mutations associated with neurological disease in NMDAR subunits have been identified in regions critical to Ca²⁺ influx. These features highlight the dynamics of Ca²⁺ influx mediated by iGluRs and its critical role in synaptic physiology and pathology.