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A new concept of CaMKII regulation and a crucial role of AKAP18δ in regulation of the heartbeat

Cathrine R. Carlson, Jan Magnus Aronsen, Anna Bergan-Dahl, Marie Christine Moutty, Marianne Lunde, Per Kristian Lunde, Hilde Jarstadmarken, Pimthanya Wanichawan, Laetitia Pereira, Terje RS Kolstad, Bjørn Dalhus, Hariharan Subramanian, Susanne Hille, Geir Christensen, Oliver J. Müller, Viacheslav Nikolaev, Donald M. Bers, Ivar Sjaastad, Xin Shen, William E. Louch, Enno Klussmann and Ole M. Sejersted

AKAP18δ anchors and regulates CaMKII activity at phospholamban-SERCA2 and RYR

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Calcium cycling inside the cardiomyocyte cells is fundamental to the heartbeat and normal heart function. The activity of the two proteins (SERCA2 and RYR) responsible for this cycling process, is regulated by the same molecule, i.e. Ca2+/calmodulin-dependent kinase type II (CaMKII). A key question in cardiac physiology has been how CaMKII interacts with these two proteins. Senior Researcher and Group Leader at IEMR Cathrine Carlson and colleagues have identified the protein (AKAP18δ) that ensures this interaction. They also show that this protein also regulates CaMKII activity itself, and thus the heartbeat. The study has recently been published in Circulation Research.

https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.120.317976

Figure. A new concept of CaMKII regulation and a crucial role of AKAP18δ in regulation of the heartbeat. The sarcoplasmic reticulum (SR) Ca2+-ATPase 2 (SERCA2) promotes cardiac relaxation, whereas the ryanodine receptor (RYR) triggers contraction. Together with several national and international collaborators, we show that the A-kinase anchoring protein (AKAP18δ) anchors CaMKII to PLN-SERCA2 and RYR, defining AKAP18δ as the first CaMKII anchoring protein. We further identify two unique regions in AKAP18δ (AKAP18δ-N and AKAP18δ-C) that inversely regulate CaMKIIδ, SERCA2 and RYR functional activities. Based on our results we propose a working model in which the two AKAP18δ regions fine-tune the Ca2+-frequency-dependent activation of CaMKIIδ at PLN-SERCA2 and RYR.

Cathrine Rein Carlson

Group Leader & Senior Researcher

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Institute for Experimental Medical Research

Oslo University Hospital, Ullevål

PB 4956 Nydalen

NO-0424 Oslo

Norway

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