{"doi":"10.1161/circresaha.120.317976","title":"AKAP18δ Anchors and Regulates CaMKII Activity at Phospholamban-SERCA2 and RYR","abstract":"Background: The sarcoplasmic reticulum (SR) Ca 2+ -ATPase 2 (SERCA2) mediates Ca 2+ reuptake into SR and thereby promotes cardiomyocyte relaxation, whereas the ryanodine receptor (RYR) mediates Ca 2+ release from SR and triggers contraction. Ca 2+ /CaMKII (CaM [calmodulin]-dependent protein kinase II) regulates activities of SERCA2 through phosphorylation of PLN (phospholamban) and RYR through direct phosphorylation. However, the mechanisms for CaMKIIδ anchoring to SERCA2-PLN and RYR and its regulation by local Ca 2+ signals remain elusive. The objective of this study was to investigate CaMKIIδ anchoring and regulation at SERCA2-PLN and RYR. Methods: A role for AKAP18δ (A-kinase anchoring protein 18δ) in CaMKIIδ anchoring and regulation was analyzed by bioinformatics, peptide arrays, cell-permeant peptide technology, immunoprecipitations, pull downs, transfections, immunoblotting, proximity ligation, FRET-based CaMKII activity and ELISA-based assays, whole cell and SR vesicle fluorescence imaging, high-resolution microscopy, adenovirus transduction, adenoassociated virus injection, structural modeling, surface plasmon resonance, and alpha screen technology. Results: Our results show that AKAP18δ anchors and directly regulates CaMKIIδ activity at SERCA2-PLN and RYR, via 2 distinct AKAP18δ regions. An N-terminal region (AKAP18δ-N) inhibited CaMKIIδ through binding of a region homologous to the natural CaMKII inhibitor peptide and the Thr17-PLN region. AKAP18δ-N also bound CaM, introducing a second level of control. Conversely, AKAP18δ-C, which shares homology to neuronal CaMKIIα activator peptide (N2B-s), activated CaMKIIδ by lowering the apparent Ca 2+ threshold for kinase activation and inducing CaM trapping. While AKAP18δ-C facilitated faster Ca 2+ reuptake by SERCA2 and Ca 2+ release through RYR, AKAP18δ-N had opposite effects. We propose a model where the 2 unique AKAP18δ regions fine-tune Ca 2+ -frequency-dependent activation of CaMKIIδ at SERCA2-PLN and RYR. Conclusions: AKAP18δ anchors and functionally regulates CaMKII activity at PLN-SERCA2 and RYR, indicating a crucial role of AKAP18δ in regulation of the heartbeat. To our knowledge, this is the first protein shown to enhance CaMKII activity in heart and also the first AKAP (A-kinase anchoring protein) reported to anchor a CaMKII isoform, defining AKAP18δ also as a CaM-KAP.","journal":"Circulation Research","year":2021,"id":155414,"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":59,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":658055,"name":"Jan Magnus Aronsen","orcid":"0000-0003-2593-1744","position":1,"is_corresponding":false},{"id":658056,"name":"Anna Bergan-Dahl","orcid":"0000-0003-1145-596X","position":2,"is_corresponding":false},{"id":659108,"name":"Marie Christine Moutty","orcid":null,"position":3,"is_corresponding":false},{"id":659109,"name":"Marianne Lunde","orcid":null,"position":4,"is_corresponding":false},{"id":382072,"name":"Per Lunde","orcid":null,"position":5,"is_corresponding":false},{"id":659110,"name":"Hilde Jarstadmarken","orcid":null,"position":6,"is_corresponding":false},{"id":659111,"name":"Pimthanya Wanichawan","orcid":null,"position":7,"is_corresponding":false},{"id":646788,"name":"Laëtitia Pereira","orcid":"0000-0002-0080-3546","position":8,"is_corresponding":false},{"id":658057,"name":"Terje R. Kolstad","orcid":"0000-0002-0589-5689","position":9,"is_corresponding":false},{"id":658058,"name":"Bjørn Dalhus","orcid":"0000-0002-9867-8391","position":10,"is_corresponding":false},{"id":299698,"name":"Hariharan Subramanian","orcid":"0000-0001-5409-4856","position":11,"is_corresponding":false},{"id":658059,"name":"Susanne Hille","orcid":"0000-0002-9809-4636","position":12,"is_corresponding":false},{"id":133319,"name":"Geir Christensen","orcid":"0000-0002-7530-0767","position":13,"is_corresponding":false},{"id":503570,"name":"Oliver J. Müller","orcid":"0000-0001-8223-2638","position":14,"is_corresponding":false},{"id":469527,"name":"Viacheslav O. Nikolaev","orcid":"0000-0002-7529-5179","position":15,"is_corresponding":false},{"id":229037,"name":"Donald M. Bers","orcid":"0000-0002-2237-9483","position":16,"is_corresponding":false},{"id":133318,"name":"Ivar Sjaastad","orcid":"0000-0002-0131-2036","position":17,"is_corresponding":false},{"id":658060,"name":"Xin Shen","orcid":"0000-0003-4429-8358","position":18,"is_corresponding":false},{"id":380698,"name":"William E. Louch","orcid":"0000-0002-0511-6112","position":19,"is_corresponding":false},{"id":658061,"name":"Enno Klußmann","orcid":"0000-0003-4004-5003","position":20,"is_corresponding":false},{"id":658062,"name":"Ole M. Sejersted","orcid":"0000-0001-8817-3296","position":21,"is_corresponding":false},{"id":658054,"name":"Cathrine R. 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