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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：
9922716
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922716
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.

总结