CaMKII activation and regulation in adult cardiac myocytes

成人心肌细胞中 CaMKII 的激活和调节

• 批准号: 10687251
• 负责人: Donald M Bers
• 金额: $ 72.12万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-18 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687251
• 关键词: Acute; Adult; Affect; Affinity; American; Animals; Arrhythmia; Binding; Binding Sites; Biochemistry; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcineurin; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cells; Chronic; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Development; Diabetes Mellitus; EFRAC; Failure; Fatty acid glycerol esters; Fluorescence Resonance Energy Transfer; Functional disorder; Gel; Gene Expression; Genetic; Genetic Transcription; Heart; Heart failure; Histone Deacetylase; Homeostasis; Hyperglycemia; Image; Individual; Ion Channel; Ions; Knock-in Mouse; Knowledge; Link; Measures; Mediating; Memory; Metabolism; Methylation; Microfilaments; Modeling; Molecular; Molecular Conformation; Muscle Cells; Mutation; NG-Nitroarginine Methyl Ester; Neurons; Nitric Oxide Synthase; Nuclear; Pathologic; Pathology; Patients; Phenotype; Phosphorylation; Phosphotransferases; Play; Post-Translational Protein Processing; Process; Production; Proteins; Regulation; Reporter; Resistance; Role; Site; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transducers; calmodulin-dependent protein kinase II; diabetic; falls; heart function; indium arsenide; innovation; mutant; novel; oxidation; preservation; pressure; prevent; response; synergism; targeted treatment

Project Summary/ Abstract Ca-Calmodulin dependent protein kinase (CaMKII) is an important regulator of cardiac function, and dysfunction in pathological states, regulating ion channels, Ca transporters, myofilaments and nuclear transcription. CaMKII may normally fine-tune these processes. But in pathological conditions like heart failure (HF), chronic autonomous CaMKII activation can over-phosphorylate targets, contributing to arrhythmogenesis due to acute effects on several ion channels and Ca- handling proteins. Chronic CaMKII activation is also a hallmark of several pathological states and acute or genetic CaMKII inhibition can reduce arrhythmias and the progression of HF. Thus understanding fundamental aspects of CaMKII regulation in cardiac myocytes is critical understanding dysfunction and potential therapeutics. We and others discovered several novel post-translational modifications (PTMs) that can trap CaMKII in an activated state, rather than turning on & off rapidly with local Ca transients. Autophosphorylation, oxidation, GlcNAcylation and S-nitrosylation within a regulatory hotspot on CaMKII creates memory and autonomous activity, even when Ca/CaM falls. There are also 3 PTMs at other sites that suppress CaMKII activation. Aims 1 and 2 will directly measure how these PTMs differentially affect activation and memory of CaMKII in adult cardiac myocytes, to fill a major knowledge gap in this field. Aim 3 will test whether CaMKII S-nitrosylation at a single site is required for the heart’s intrinsic response to increase Ca transients and contraction in response to acute and chronic pressure overload (or the Anrep effect). CaMKII has well-recognized roles in HF with reduced ejection (HFrEF), but its role in HF with preserved ejection (HFpEF) is unclear. Aim 4 will directly test the engagement of CaMKII in two new HFpEF models. The proposed studies will have major impact on our understanding of how CaMKII activity is regulated in heart, in ways that promote pathology and might be targets for therapeutic intervention.

项目总结/摘要 钙调素依赖性蛋白激酶（CaMKII）是心脏功能的重要调节因子， 在病理状态下，调节离子通道、钙转运体、肌丝 和核转录。CaMKII通常可以微调这些过程。但在病理学上， 如心力衰竭（HF）等疾病，慢性自主CaMKII激活可过度磷酸化 靶点，由于对几种离子通道和Ca- 处理蛋白质慢性CaMKII激活也是几种病理状态的标志 急性或遗传性CaMKII抑制可减少心律失常和HF的进展。因此 理解心肌细胞中CaMKII调节的基本方面是至关重要的 了解功能障碍和潜在的治疗方法。我们和其他人发现了几个新的 翻译后修饰（PTM）可以将CaMKII捕获在激活状态，而不是 在局部钙瞬变的情况下快速开启和关闭。自磷酸化、氧化、GlcNAc酰化 和S-亚硝基化在CaMKII上的调节热点内产生记忆和自主 活性，即使当Ca/CaM福尔斯下降。在其他位点也有3个PTM抑制CaMKII activation.目标1和2将直接测量这些PTM如何差异性地影响激活， 在成人心肌细胞中的CaMKII的记忆，以填补在这一领域的主要知识空白。目标3 将测试CaMKII的S-亚硝基化是否需要在一个单一的网站，为心脏的内在 对急性和慢性压力反应的钙瞬变和收缩增加的反应 超负荷（或Anrep效应）。CaMKII在射血减少的HF中具有公认的作用 （HFrEF），但其在保留射血功能的HF（HFpEF）中的作用尚不清楚。目标4将直接测试 CaMKII在两个新的HFpEF模型中的参与。拟议的研究将产生重大影响 我们对CaMKII活性如何在心脏中调节的理解， 病理学，可能是治疗干预的目标。

项目成果

Neuron-Restrictive Silencer Factor Limits Myocyte GαO Expression and Is Protective in Heart Failure Progression.

神经元限制性沉默因子限制肌细胞 GαO 表达并在心力衰竭进展中具有保护作用。

• DOI: 10.1161/circresaha.121.320597
• 发表时间: 2022
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Sossalla,Samuel;Bers,DonaldM
• 通讯作者: Bers,DonaldM

Cardiac CaMKII activation promotes rapid translocation to its extra-dyadic targets.

• DOI: 10.1016/j.yjmcc.2018.10.010
• 发表时间: 2018-12
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Wood BM;Simon M;Galice S;Alim CC;Ferrero M;Pinna NN;Bers DM;Bossuyt J
• 通讯作者: Bossuyt J

CaMKII and PKA-dependent phosphorylation co-regulate nuclear localization of HDAC4 in adult cardiomyocytes.

CaMKII 和 PKA 依赖性磷酸化共同调节成体心肌细胞中 HDAC4 的核定位。

• DOI: 10.1007/s00395-021-00850-2
• 发表时间: 2021-02-15
• 期刊: Basic research in cardiology
• 影响因子: 9.5
• 作者: Helmstadter KG;Ljubojevic-Holzer S;Wood BM;Taheri KD;Sedej S;Erickson JR;Bossuyt J;Bers DM
• 通讯作者: Bers DM

Quantitative cross-species translators of cardiac myocyte electrophysiology: Model training, experimental validation, and applications.

• DOI: 10.1126/sciadv.abg0927
• 发表时间: 2021-11-19
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Morotti S;Liu C;Hegyi B;Ni H;Fogli Iseppe A;Wang L;Pritoni M;Ripplinger CM;Bers DM;Edwards AG;Grandi E
• 通讯作者: Grandi E

Mechanoelectric coupling and arrhythmogenesis in cardiomyocytes contracting under mechanical afterload in a 3D viscoelastic hydrogel.

• DOI: 10.1073/pnas.2108484118
• 发表时间: 2021-08-03
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Hegyi B;Shimkunas R;Jian Z;Izu LT;Bers DM;Chen-Izu Y
• 通讯作者: Chen-Izu Y