The Extracellular Domains of the AMPA, Kainate, And Orphan Delta Receptor Regulate Channel Gating in Distinct Ways

The ionotropic glutamate receptors are ligand-gated cationic channels essential for neuroplasticity and neurological functions such as learning, memory, behavior, cognition, and motor coordination. Mutations in these channels are linked to various disorders including autism, ataxia, and epilepsy, making them compelling pharmacological targets. Within this family, the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate receptor mediate their function through fast glutamate-gated ionotropic activity, which needs precise structural changes to perform properly. While Cryo-EM structures have provided snap shots of these proteins, questions remain regarding the dynamics across conformations and individual roles of the extracellular amino-terminal and agonist binding domain in dictating function. Specifically, how these domains contribute to modulation in function by modulators such as pH and binding proteins, including those involved in trans-synaptic connections, remain largely unknown. Here, I investigate the structure-function relationships of the extracellular domains in the AMPA, kainate, and orphan delta receptor, all which create trans-synaptic complexes in the brain. My studies reveal that coupling of the extracellular domains increases the intrinsic activity of the AMPA and kainate receptor and induces the delta receptor to have intrinsic ligand-gated activity. In addition, these studies reveal a novel mechanism of inhibition produced by protonation and perampanel-like drugs. Taken together, this work provides new insights into the distinct roles of the extracellular amino-terminal domain and the agonist-binding domain.