{"doi":"10.1101/2022.09.25.509219","title":"Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics","abstract":"Abstract AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an opportunity for the development of selective therapeutics. AMPARs associated with TARP γ8 are enriched in the hippocampus, and are targets of emerging anti-epileptic drugs. To understand their therapeutic activity, we determined cryo-EM structures of the GluA1/2-γ8 receptor associated with three potent, chemically diverse drugs. We find that despite sharing a lipid-exposed and water-accessible binding pocket, drug action is differentially affected by binding-site mutants. Together with patch-clamp recordings and MD simulations we demonstrate that ligand-triggered reorganisation of the AMPAR-TARP interface contributes to modulation. Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":304385,"datarank":0.12260632455272946,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.01863424746873766,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.01863424746873766,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":627669,"name":"Remigijus Lapė","orcid":"0000-0002-6604-0828","position":1,"is_corresponding":false},{"id":997230,"name":"Saher A. Shaikh","orcid":"0000-0002-6162-5472","position":2,"is_corresponding":false},{"id":997783,"name":"Bianka K. Kohegyi","orcid":null,"position":3,"is_corresponding":false},{"id":997231,"name":"Jake F. Watson","orcid":"0000-0002-8698-3823","position":4,"is_corresponding":false},{"id":997784,"name":"Ondřej Cais","orcid":null,"position":5,"is_corresponding":false},{"id":345761,"name":"Terunaga Nakagawa","orcid":"0000-0001-6174-5012","position":6,"is_corresponding":false},{"id":997232,"name":"Ingo H. Greger","orcid":"0000-0002-7291-2581","position":7,"is_corresponding":false},{"id":997229,"name":"Danyang Zhang","orcid":"0000-0003-1280-9248","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:32:32.651796Z","pmid":null,"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":[]}