1. Department of Neurobiology, Affiliated Mental Health Center and Hangzhou Seventh People’s Hospital and Liangzhu Laboratory, School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China
2. MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou 311121, China
3. Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
Corresponding author:
0621309@zju.edu.cn
0622B12@zju.edu.cn
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History+
Received
Accepted
Published Online
2025-12-22
2026-06-02
2026-10-16
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(1995KB)
Abstract
Calcium/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional serine/threonine kinase that plays an important role in regulating intracellular calcium (Ca2+) handling in the heart. By phosphorylating calcium-handling protein on the sarcoplasmic reticulum (SR) and mitochondria, CaMKII modulates excitation–contraction coupling, mitochondrial homeostasis, and cell survival pathways. Pathologically, chronic CaMKII activation contributes to calcium mishandling, oxidative stress, and maladaptive cardiac remodeling which exacerbate myocardial infarction, arrhythmias, and other cardiac dysfunctions. Recent advances in understanding the molecular mechanisms of CaMKII regulation and its pathological activation have opened new avenues for therapeutic intervention. This review discusses the molecular mechanisms by which CaMKII phosphorylates key Ca2+-handling proteins in the SR and mitochondria, including ryanodine receptor 2 (RyR2) at Ser2814 and the mitochondrial calcium uniporter (MCU) at Ser57/Ser92, with evidence support from biochemical, cellular, and in vivo studies, and further summarizes its role in maintaining calcium homeostasis, and highlights emerging therapeutic strategies targeting CaMKII to improve cardiac function and mitigate disease progression from bench to clinic.
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