Molecular Regulation of cardiac adrenergic signaling

心脏肾上腺素信号传导的分子调节

• 批准号: 10155584
• 负责人: YANG K XIANG
• 金额: $ 43.54万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155584
• 关键词: A kinase anchoring protein; Adrenergic Agents; Adrenergic Receptor; Agonist; Apoptosis; Arrhythmia; Attenuated; Binding; C-terminal; Calcium; Cardiac; Cardiac Myocytes; Cardiotoxicity; Chronic; Complex; Coupling; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DLG1 gene; Data; Development; Disease; Dissociation; Ensure; Exposure to; Functional disorder; GRK5 gene; GTP-Binding Proteins; Heart; Heart Contractilities; Heart failure; Hypertrophy; Isoproterenol; L-Type Calcium Channels; Link; Modeling; Molecular; Mus; Muscle Cells; Orphan; Perfusion; Periodicity; Pharmacology; Phosphorylation; Phosphotransferases; Physiological; Physiology; Play; Production; Regulation; Role; Sarcoplasmic Reticulum; Scaffolding Protein; Serine; Signal Transduction; Stress; Testing; Transgenes; Transgenic Mice; Transgenic Organisms; Treatment Failure; beta-adrenergic receptor; biological adaptation to stress; calmodulin-dependent protein kinase II; constriction; cytotoxicity; genetic predictors; heart function; insight; mouse model; mutant; novel; phosphoric diester hydrolase; preservation; pressure; receptor; response; scaffold; therapeutic target; tool

Summary β adrenergic receptors (βARs) are critical for cardiac function and are linked to HF. Chronic β1AR-cAMP signaling promotes activation of CaMKII, which is requisite for all the detrimental effects during maladaptive remodeling in heart. However, the mechanism governing this specific signaling regulation by β1AR in HF development is still incompletely understood. We aim to reveal a novel supercomplex of cardiac beta1 adrenergic receptor that is orchestrated by scaffold protein SAP97 and connects to L-type calcium channel directly. Moreover, SAP97 also scaffold AKAP79/PKA and PDE4D8 in the complex to ensure rapid and robust regulation of L-type calcium channel in local vicinity, which is essential to maintain rhythmic beat-to- to-beat cardiac contraction during stress response. We aim to gain insight of regulation of this sophisticated beta1 adrenergic receptor supercomplex in spatially differentiated cardiac myocytes and explore the dissemble and dysfunction of this complex in disease development via promoting cytotoxicity in heart. We hypothesize that GRK5 acts as a molecular switch to turn on Epac-dependent activation of CaMKII. We have generated mice to simulate dissociation of the b1AR-SAP97 complex and to study SAP97-dependent b1AR signaling in physiology and diseases. This study will provide new insight governing the specific b1AR signaling involved in physiology an in HF, and offer GRK5 as a complementary therapeutic target for HF. The hypothesis will be examined in the following aims: Aim 1. A SAP97 complex facilitates PKA-dependent regulation of EC coupling. Aim 2. Disruption of b1AR-SAP97 interaction promotes b1AR-induced CaMKII activity. Aim 3. GRK5 phosphorylation of b1AR at S475 controls the binding of b1AR to SAP97 to gate cardiotoxic CaMKII in HF.

摘要 β肾上腺素能受体(βAR)对心功能起关键作用，并与心衰有关。慢性β1AR-cAMP 信号促进CaMKII的激活，这是适应不良期间所有有害影响所必需的 心脏重塑。然而，β1AR在HF中控制这一特定信号调节的机制 人们对发展的理解仍然不完全。我们的目标是揭示一种新的心脏β1超复合体 连接L钙通道的由支架蛋白SAP97调控的肾上腺素能受体 直接去吧。此外，SAP97还在建筑群中搭建了AKAP79/PKA和PDE4D8支架，以确保快速和 局部L型钙通道的强健调节是维持节律性心动过速所必需的 在应激反应中跳动心脏收缩。我们的目标是深入了解这一复杂的 β1肾上腺素能受体超复合体在空间分化的心肌细胞中的表达 通过促进心脏中的细胞毒作用来掩盖和功能这种复合体在疾病发展中的作用。我们 假设GRK5作为分子开关开启EPAC依赖的CaMKII激活。我们 已经建立了小鼠来模拟b1AR-SAP97复合体的解离，并研究SAP97依赖 B1AR信号在生理和疾病中的作用。这项研究将为管理特定的b1AR提供新的见解 参与生理学和心力衰竭的信号转导，并提供GRK5作为心力衰竭的补充治疗靶点。 这一假说将在以下目标中得到验证：目标1.SAP97复合体促进PKA依赖 EC联结的调控。目的2.阻断b1AR-SAP97相互作用促进b1AR诱导的CaMKII 活动。目的3.b1AR在S475处的GRK5磷酸化控制b1AR与SAP97与GATE的结合 心毒性CaMKII在HF中。