Desensitization of beta1 adrenergic receptor-nitric oxide signaling in cardiac diseases

心脏病中β1肾上腺素受体-一氧化氮信号的脱敏

基本信息

批准号：
10618826
负责人：
YANG K XIANG
金额：
--
依托单位：
VA NORTHERN CALIFORNIA HEALTH CARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618826
关键词：
Address Adrenergic Agents Adrenergic Receptor Agonist Attenuated Binding Biochemistry Biological Assay Biosensor C-terminal Calcium Cardiac Cardiac Output Cardiomyopathies Chronic Co-Immunoprecipitations Complex Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Cyclic GMP-Dependent Protein Kinases Data Disease Dissociation Electrophysiology (science)Enzyme-Linked Immunosorbent Assay Epinephrine Fluorescence Resonance Energy Transfer Fluorescent Dyes Functional disorder G-substrate GTP-Binding Proteins Health Heart Heart Diseases Heart failure Human Impairment Individual Knock-in Knock-out Knockout Mice Knowledge Muscle Cells Myocardial Myocardial Infarction Myocardial dysfunction NOS1 gene NOS3 gene Nitric Oxide Nitric Oxide Synthase Optics Pathway interactions Phosphorylation Phosphotransferases Physiological Play Proteins Receptor Signaling Recovery Regulation Research Role Ryanodine Receptor Calcium Release Channel Scaffolding Protein Serine Signal Transduction Signaling Molecule Soluble Guanylate Cyclase Stress Synapses Synaptic Receptors Techniques Testing Transgenic Mice Transgenic Organisms adrenergic stress aorta constriction desensitization heart function heart preservation in vivo inhibitor innovation novel novel strategies phosphodiesterase 4D phospholamban preservation receptor restoration

项目摘要

Emerging evidence indicates that nitric oxide (NO) is involved in cardiac β1 adrenergic receptor (β1AR) stimulation of cardiac function. We propose that scaffold protein SAP97 plays a critical role in regulation of cardiac β1AR-induced NOS1-NO signaling cascade via organizing a β1AR- NOS1 signalosome. This pathway is necessary for regulation of cardiac contractile function. We also hypothesize that G-protein kinase 5 (GRK5) promotes phosphorylation of cardiac β1AR PDZ motif and dissociation of the receptor from the SAP97-organized signalosome for activation of NOS1-NO signaling and promotes desensitization of receptor signaling in cardiac diseases. We will test the hypotheses with the following aims. Aim 1. SAP97 regulates β1AR-induced NO signaling in heart. Aim 2. SAP97 maintains the integrity of β1AR-SAP97-NOS1 signalosome to preserve cardiac function. Aim 3. GRK5 promotes desensitization of β1AR-NO signaling via disruption of the receptor-SAP97 signalosome in heart failure.

新证据表明一氧化氮 (NO) 参与心脏 β1 肾上腺素能受体 (β1AR) 刺激心脏功能我们认为支架蛋白 SAP97 发挥着关键作用。通过组织β1AR-在调节心脏β1AR诱导的NOS1-NO信号级联中的作用 NOS1 信号体是调节心脏收缩功能所必需的。还发现 G 蛋白激酶 5 (GRK5) 促进心脏 β1AR 磷酸化 PDZ 基序和受体从 SAP97 组织的信号体解离以进行激活 NOS1-NO 信号传导并促进心脏病中受体信号传导的脱敏。我们将测试以下目标的假设：SAP97 调节 β1AR 诱导的 NO。目标 2. SAP97 维持 β1AR-SAP97-NOS1 信号体的完整性目标 3。GRK5 通过促进 β1AR-NO 信号脱敏。心力衰竭中受体 SAP97 信号体的破坏。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Divergent Actions of Myofibroblast and Myocyte β2-Adrenoceptor in Heart Failure and Fibrotic Remodeling.

肌成纤维细胞和肌细胞β2-肾上腺素受体在心力衰竭和纤维化重塑中的不同作用。

DOI：
发表时间：
2023-01-06
期刊：
影响因子：
20.1
作者：
Deng, Bingqing;Zhang, Yu;Zhu, Chaoqun;Wang, Ying;Weatherford, Eric;Xu, Bing;Liu, Xianhui;Conway, Simon J;Abel, E. Dale;Xiang, Yang K
通讯作者：
Xiang, Yang K

Monoamine oxidase A and organic cation transporter 3 coordinate intracellular β1AR signaling to calibrate cardiac contractile function.

单胺氧化酶 A 和有机阳离子转运蛋白 3 协调细胞内 β1AR 信号传导以校准心脏收缩功能。

DOI：
发表时间：
2022-07-17
期刊：
影响因子：
9.5
作者：
Wang, Ying;Zhao, Meimi;Xu, Bing;Bahriz, Sherif M F;Zhu, Chaoqun;Jovanovic, Aleksandra;Ni, Haibo;Jacobi, Ariel;Kaludercic, Nina;Di Lisa, Fabio;Hell, Johannes W;Shih, Jean C;Paolocci, Nazareno;Xiang, Yang K
通讯作者：
Xiang, Yang K

Monoamine Oxidases Desensitize Intracellular β1AR Signaling in Heart Failure.

单胺氧化酶使心力衰竭中细胞内β1AR 信号转导脱敏。