• Medientyp: E-Artikel
  • Titel: AKAP18δ Anchors and Regulates CaMKII Activity at Phospholamban-SERCA2 and RYR
  • Beteiligte: Carlson, Cathrine R.; Aronsen, Jan Magnus; Bergan-Dahl, Anna; Moutty, Marie Christine; Lunde, Marianne; Lunde, Per Kristian; Jarstadmarken, Hilde; Wanichawan, Pimthanya; Pereira, Laetitia; Kolstad, Terje R.S.; Dalhus, Bjørn; Subramanian, Hariharan; Hille, Susanne; Christensen, Geir; Müller, Oliver J.; Nikolaev, Viacheslav; Bers, Donald M.; Sjaastad, Ivar; Shen, Xin; Louch, William E.; Klussmann, Enno; Sejersted, Ole M.
  • Erschienen: Ovid Technologies (Wolters Kluwer Health), 2022
  • Erschienen in: Circulation Research
  • Sprache: Englisch
  • DOI: 10.1161/circresaha.120.317976
  • ISSN: 0009-7330; 1524-4571
  • Schlagwörter: Cardiology and Cardiovascular Medicine ; Physiology
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  • Beschreibung: <jats:sec> <jats:title>Background:</jats:title> <jats:p> The sarcoplasmic reticulum (SR) Ca <jats:sup>2+</jats:sup> -ATPase 2 (SERCA2) mediates Ca <jats:sup>2+</jats:sup> reuptake into SR and thereby promotes cardiomyocyte relaxation, whereas the ryanodine receptor (RYR) mediates Ca <jats:sup>2+</jats:sup> release from SR and triggers contraction. Ca <jats:sup>2+</jats:sup> /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 <jats:sup>2+</jats:sup> signals remain elusive. The objective of this study was to investigate CaMKIIδ anchoring and regulation at SERCA2-PLN and RYR. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> 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 <jats:sup>2+</jats:sup> threshold for kinase activation and inducing CaM trapping. While AKAP18δ-C facilitated faster Ca <jats:sup>2+</jats:sup> reuptake by SERCA2 and Ca <jats:sup>2+</jats:sup> release through RYR, AKAP18δ-N had opposite effects. We propose a model where the 2 unique AKAP18δ regions fine-tune Ca <jats:sup>2+</jats:sup> -frequency-dependent activation of CaMKIIδ at SERCA2-PLN and RYR. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>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.</jats:p> </jats:sec>
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