Molecular Regulation of cardiac adrenergic signaling

心脏肾上腺素信号传导的分子调节

基本信息

批准号：
10425249
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10425249
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

项目摘要

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.

概括 β 肾上腺素能受体 (βAR) 对心脏功能至关重要，并与慢性 β1AR-cAMP 相关。信号传导促进 CaMKII 的激活，这是适应不良期间所有不健康影响所必需的然而，HF 中 β1AR 控制这种特定信号传导的机制。我们的目标是揭示心脏β1的新型超级复合物。由支架蛋白 SAP97 协调并连接到 L 型钙通道的肾上腺素受体此外，SAP97还在复合物中直接支架AKAP79/PKA和PDE4D8以确保快速和有效。局部附近 L 型钙通道的强有力调节，这对于维持节律性搏动至关重要我们的目标是了解这种复杂的调节过程。空间分化心肌细胞中的β1肾上腺素受体超复合物并探索通过促进心脏细胞毒性，该复合物在疾病发展中发生分解和功能障碍。我们发现 GRK5 作为分子开关来开启 CaMKII 的 Epac 依赖性激活。已经培育出小鼠来模拟 b1AR-SAP97 复合物的解离并研究 SAP97 依赖性生理学和疾病中的 b1AR 信号传导这项研究将为控制特定 b1AR 提供新的见解。 HF 中涉及生理学的信号传导，并提供 GRK5 作为 HF 的补充治疗靶点。该假设将在以下目标中进行检验：目标 1. SAP97 复合体促进 PKA 依赖性 EC 偶联的调节。目标 2. b1AR-SAP97 相互作用的破坏促进 b1AR 诱导的 CaMKII 目标 3。b1AR 在 S475 处的 GRK5 磷酸化控制 b1AR 与 SAP97 的结合。 HF 中的心脏毒性 CaMKII。