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）对于心脏功能至关重要，与HF有关。慢性β1AR训练营信号传导促进CAMKII的激活，这是适应不良期间所有有害效应的必要条件内心重塑。但是，管理HF中β1AR的特定信号调节的机制发展仍然不完全理解。我们旨在揭示心脏Beta1的新型超复合物由支架蛋白SAP97策划并连接到L型钙通道的肾上腺素受体直接地。此外，SAP97在该建筑群中还脚手架AKAP79/PKA和PDE4D8，以确保快速和局部附近L型钙通道的强大调节，这对于维持节奏的节奏至关重要压力反应期间的抗肌肉收缩。我们旨在了解对这一复杂的调节 Beta1肾上腺素受体超复合在空间分化的心肌细胞中，并探索通过促进心脏的细胞毒性，这种复合物在疾病发育中的分散和功能障碍。我们假设GRK5充当分子开关，可以打开CAMKII的EPAC依赖性激活。我们已经产生了小鼠以模拟B1AR-SAP97复合物的解离并研究SAP97依赖性生理和疾病中的B1AR信号传导。这项研究将提供有关特定B1AR的新见解涉及HF的生理学的信号传导，并提供GRK5作为HF的完整治疗靶标。该假设将在以下目的中进行检查：目标1。SAP97复杂的最爱PKA依赖性PKA EC耦合的调节。目标2。b1AR-SAP97相互作用的破坏促进了B1AR诱导的CAMKII 活动。 AIM3。B1AR在S475上的GRK5磷酸化控制B1AR与SAP97与Gate的结合 HF中的心脏毒性CAMKII。