{"doi":"10.1101/2025.06.27.662003","title":"Mechanisms of Ion Permeation in the AMPA Receptor Ion Channel","abstract":"Abstract 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 Ca 2+ 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 Ca 2+ 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 Zn 2+ block but also creates a more energetically favorable environment for Na + and Ca 2+ 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":556500,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9617,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":406694,"name":"Remy A. Yovanno","orcid":"0000-0003-3852-6684","position":1,"is_corresponding":false},{"id":406695,"name":"Albert Y. Lau","orcid":"0000-0002-0967-7558","position":2,"is_corresponding":false},{"id":1168365,"name":"Edward C. Twomey","orcid":"0000-0002-1855-1586","position":3,"is_corresponding":false},{"id":885425,"name":"Alejandra Montaño Romero","orcid":null,"position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-19T02:55:08.896385Z","pmid":"40631165","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}