CaMKII activation and regulation in adult cardiac myocytes

项目摘要/摘要 钙调素依赖蛋白激酶(CaMKII)是一种重要的心功能调节因子， 以及病理状态下的功能障碍，调节离子通道、钙转运体、肌丝 和核转录。CaMKII通常可能会微调这些过程。但在病理性方面 心力衰竭(HF)、慢性自主激活CaMKII可过度磷酸化 靶点，由于几个离子通道和钙离子的急性作用而导致心律失常。 处理蛋白质。慢性CaMKII激活也是几种病理状态的标志 急性或遗传的CaMKII抑制可以减少心律失常和心力衰竭的进展。因此， 了解心肌细胞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一些小说 翻译后修饰(PTM)可以使CaMKII处于激活状态，而不是 通过局部钙瞬变快速开启和关闭。自动磷酸化、氧化、GlcN酰化 而S-CaMKII调控热点内的亚硝酸化产生记忆和自主 活动，即使当钙/钙下降。在其他部位也有3个PTM抑制CaMKII 激活。AIMS 1和2将直接测量这些PTM如何不同地影响激活和 CaMKII在成人心肌细胞中的记忆，填补了这一领域的一个重大知识空白。目标3 将测试是否需要在单个部位进行CaMKII S亚硝化反应来实现心脏的内在功能 对急性和慢性压力下钙瞬变和收缩增加的反应 过载(或安雷普效应)。CaMKII在减少射血的心衰中具有公认的作用 (HFrEF)，但其在射血功能保留的心衰(HFpEF)中的作用尚不清楚。AIM 4将直接测试 CaMKII在两个新的HFpEF模型中的接洽。拟议的研究将产生重大影响 关于我们对CaMKII活性是如何在心脏中以促进 并可能成为治疗干预的靶点。

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.