{"doi":"10.1172/jci193349","title":"Spinal α2δ-1 induces GluA3 degradation to regulate assembly of calcium-permeable AMPA receptors and pain hypersensitivity","abstract":"The increased prevalence of GluA2-lacking, Ca2+-permeable AMPA receptors (CP-AMPARs) at spinal cord sensory synapses amplifies nociceptive transmission and maintains chronic neuropathic pain. Nerve injury-induced upregulation of α2δ-1 disrupts the assembly of GluA1/GluA2 heteromers, favoring the synaptic incorporation of GluA1 homotetramers in the spinal dorsal horn. Although GluA1-GluA3 subunits are broadly expressed, whether α2δ-1 regulates GluA3-containing AMPARs remains unknown. Here, we unexpectedly found that coexpression with α2δ-1 - but not α2δ-2 or α2δ-3 - diminished GluA3 AMPAR currents and protein levels, an effect blocked by pregabalin, an α2δ-1 C-terminus peptide, or proteasome inhibition. Both nerve injury and α2δ-1 overexpression reduced protein levels of GluA3 and GluA2/GluA3 heteromers in the spinal cord. Furthermore, α2δ-1 coexpression or nerve injury increased GluA3 ubiquitination, with K861 at the C-terminus of GluA3 identified as a key ubiquitination site mediating α2δ-1-induced GluA3 degradation. Additionally, intrathecal delivery of the Gria3 gene reversed nerve injury-induced nociceptive hypersensitivity and synaptic CP-AMPARs by restoring protein levels of GluA3 and GluA2/GluA3 heteromers in the spinal cord. These findings reveal that α2δ-1 promotes GluA1 homotetramer assembly and synaptic CP-AMPAR expression by driving ubiquitin-proteasome-mediated degradation of GluA3, providing insights into the molecular mechanisms of neuropathic pain and the therapeutic actions of gabapentinoids.","journal":"Journal of Clinical Investigation","year":2025,"id":527286,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9457,"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":351825,"name":"Shao-Rui Chen","orcid":"0000-0002-0426-8202","position":1,"is_corresponding":false},{"id":686911,"name":"Daozhong Jin","orcid":"0000-0002-6304-2713","position":2,"is_corresponding":false},{"id":1290465,"name":"Yuying Huang","orcid":"0000-0001-8783-198X","position":3,"is_corresponding":false},{"id":680436,"name":"Hong Chen","orcid":"0000-0001-8054-7417","position":4,"is_corresponding":false},{"id":1034763,"name":"Guanxing Chen","orcid":"0000-0002-4435-0884","position":5,"is_corresponding":false},{"id":565801,"name":"Jiusheng Yan","orcid":"0000-0002-6633-1799","position":6,"is_corresponding":false},{"id":351826,"name":"Hui‐Lin Pan","orcid":"0000-0001-8444-3770","position":7,"is_corresponding":false},{"id":680435,"name":"Menghua Zhou","orcid":"0000-0002-3396-5269","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:50:39.280101Z","pmid":"41129242","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":[]}