{"doi":"10.1016/j.molpha.2025.100029","title":"The neuroprotective γ-hydroxybutyrate analog 3-hydroxycyclopent-1-enecarboxylic acid does not directly affect CaMKIIα autophosphorylation at T286 or binding to GluN2B","abstract":"The Ca 2+ /calmodulin (CaM)-dependent protein kinase II (CaMKII) mediates physiological long-term potentiation (LTP) of synaptic strength and pathological ischemic neuronal cell death. Both functions require CaMKII autophosphorylation at T286 (pT286) and binding to the NMDA-type glutamate receptor subunit GluN2B. The neuroprotection seen with 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) was thought to be mediated by impairing binding of the brain-specific CaMKII α isozyme to GluN2B. However, we show that HOCPCA does not inhibit CaMKII α enzymatic activity, pT286, cocondensation with GluN2B, or binding to GluN2B. Consistent with no effect on GluN2B binding in vitro or in HEK293 cells, HOCPCA also did not affect the CaMKII α movement to excitatory synapses in hippocampal neurons in response to LTP stimuli. These findings leave the neuroprotective mechanism of HOCPCA unclear but explain why HOCPCA does not impair LTP. Significance Statement This study found that the neuroprotective compound 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) does not directly interfere with Ca 2+ /calmodulin (CaM)-dependent protein kinase II (CaMKII) activity or GluN2B binding. Although this leaves the neuroprotective mechanism of HOCPCA unclear, it explains why HOCPCA does not impair long-term potentiation. Overall, this limits the use of HOCPCA as a tool compound to study CaMKII functions, but not its clinical potential.","journal":"Molecular Pharmacology","year":2025,"id":562927,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"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":737198,"name":"Rachel E. Blaine","orcid":"0000-0003-3561-7601","position":1,"is_corresponding":false},{"id":1222870,"name":"C. Madison Barker","orcid":"0000-0003-3329-5370","position":2,"is_corresponding":false},{"id":345715,"name":"Steven J. Coultrap","orcid":"0009-0005-7272-6358","position":3,"is_corresponding":false},{"id":345718,"name":"K. Ulrich Bayer","orcid":"0000-0003-0893-2200","position":4,"is_corresponding":false},{"id":416627,"name":"Carolyn Nicole Brown","orcid":"0000-0002-3612-1125","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:56:09.638214Z","pmid":"40184780","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":[]}