Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; email:
Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA.
Annu Rev Pharmacol Toxicol. 2023 Jan 20;63:249-272. doi: 10.1146/annurev-pharmtox-051421-111814. Epub 2022 Aug 16.
CaMKII (the multifunctional Ca and calmodulin-dependent protein kinase II) is a highly validated signal for promoting a variety of common diseases, particularly in the cardiovascular system. Despite substantial amounts of convincing preclinical data, CaMKII inhibitors have yet to emerge in clinical practice. Therapeutic inhibition is challenged by the diversity of CaMKII isoforms and splice variants and by physiological CaMKII activity that contributes to learning and memory. Thus, uncoupling the harmful and beneficial aspects of CaMKII will be paramount to developing effective therapies. In the last decade, several targeting strategies have emerged, including small molecules, peptides, and nucleotides, which hold promise in discriminating pathological from physiological CaMKII activity. Here we review the cellular and molecular biology of CaMKII, discuss its role in physiological and pathological signaling, and consider new findings and approaches for developing CaMKII therapeutics.
钙调蛋白依赖性蛋白激酶 II（CaMKII，多功能 Ca2+和钙调蛋白依赖性蛋白激酶 II）是一种经过充分验证的信号，可促进多种常见疾病，特别是心血管系统疾病的发生。尽管有大量令人信服的临床前数据，但 CaMKII 抑制剂尚未在临床实践中出现。CaMKII 异构体和剪接变体的多样性以及对学习和记忆有贡献的生理 CaMKII 活性对治疗抑制构成了挑战。因此，解开 CaMKII 的有害和有益方面对于开发有效的治疗方法至关重要。在过去的十年中，出现了几种靶向策略，包括小分子、肽和核苷酸，它们有望区分病理性和生理性 CaMKII 活性。本文综述了 CaMKII 的细胞和分子生物学，讨论了其在生理和病理信号转导中的作用，并考虑了开发 CaMKII 治疗药物的新发现和方法。
