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: 9905549
• 负责人: Donald M Bers
• 金额: $ 62.77万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905549
• 关键词: Acute; Adult; Affect; Affinity; American; Animals; Arrhythmia; Biochemistry; Biological Assay; Biotinylation; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcineurin; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Chronic; Clinical; Cyclic AMP-Dependent Protein Kinases; Data; Enzymes; Failure; Female; Fluorescence; Fluorescence Resonance Energy Transfer; Functional disorder; Gene Expression; Genetic; Genetic Transcription; Heart; Heart failure; Histone Deacetylase; Holoenzymes; Hyperglycemia; Hypertrophy; Image; Individual; Ion Channel; Ischemia; Knock-in Mouse; Knowledge; Label; Location; Measures; Memory; Metabolism; Methods; Microfilaments; Modification; Molecular; Movement; Mus; Muscle Cells; Neurons; Nitric Oxide Synthase; Nuclear; Oxidative Stress; Pathologic; Pathology; Phosphotransferases; Physiological; Post-Translational Modification Site; Post-Translational Protein Processing; Process; Proteins; Regulation; Reperfusion Therapy; Reporter; Resistance; Role; Runaway; Site; Stress; Testing; Therapeutic; Therapeutic Intervention; Time; Variant; base; calmodulin-dependent protein kinase II; cardiogenesis; diabetic; falls; heart function; indium arsenide; innovation; monomer; mutant; novel; oxidation; pressure; synergism; targeted treatment; tool

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 chronic autonomous CaMKII over-activation can hyerphosphorylate 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. The functional synergy among these PTMs is unknown, but will be directly measured in myocytes in Aim 1. Dogma has been that CaMKII-dodecamers neither exchange subunits nor move appreciably in myocytes, but our preliminary data upends both dogmas, and this will be elucidated in Aim 2. S-nitrosylation, the newest regulatory PTM, can either promote autonomous activation (C290) or inhibit Ca/CaM activation (C273). Aim 3 will test the functional impact of these sites in adult myocytes and in acute ischemia/reperfusion and long-term pressure overload in intact animals. We will use multiple innovative fluorescence tools and methods, and animals to test these 3 major CaMKII Aims. 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.

项目概要/摘要 Ca-钙调蛋白依赖性蛋白激酶 (CaMKII) 是心脏功能的重要调节因子， 和病理状态下的功能障碍，调节离子通道、钙转运蛋白、肌丝 CaMKII 通常可以微调这些过程，但在病理情况下。 慢性自主性 CaMKII 过度激活可以使靶标过度磷酸化， 由于对多个离子通道和 Ca 处理的急性影响，导致心律失常 慢性 CaMKII 激活也是多种病理状态和急性状态的标志。 或基因 CaMKII 抑制可以减少心律失常和心力衰竭的进展。 了解心肌细胞 CaMKII 调节的基本方面至关重要 我们和其他人发现了一些新奇的东西。 翻译后修饰 (PTM) 可以将 CaMKII 捕获在激活状态，而不是 通过局部 Ca 瞬变快速打开和关闭。 CaMKII 调控热点内的 S-亚硝基化可创造记忆和自主能力 即使当 Ca/CaM 下降时，这些 PTM 之间的功能协同作用尚不清楚，但 将在目标 1 中直接测量肌细胞。教条是 CaMKII-十二聚体 既不交换亚单位，也不在肌细胞中明显移动，但我们的初步数据颠覆了 两个教条，这将在目标 2 中得到阐明。S-亚硝基化，最新的监管 PTM， 可以促进自主激活 (C290) 或抑制 Ca/CaM 激活 (C273)。 将测试这些位点对成体肌细胞和急性缺血/再灌注的功能影响 我们将使用创新的多重荧光。 测试这 3 个主要 CaMKII 的工具和方法以及动物。拟议的研究将。 对我们理解 CaMKII 活性如何在心脏中进行调节产生重大影响 促进病理学并可能成为治疗干预的目标。