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.

新兴证据表明，一氧化氮（NO）参与心脏β1肾上腺素受体（β1AR）刺激心脏功能。我们建议支架蛋白SAP97发挥着关键的作用通过组织β1AR- NOS1信号体。该途径对于调节心脏收缩功能是必需的。我们还假设G蛋白激酶5（GRK5）促进心脏β1AR的磷酸化 PDZ基序和接收器与SAP97组织的信号体的解离以激活 NOS1-NO信号传导并促进心脏疾病中受体信号传导的脱敏。我们将以以下目的测试假设。 AIM1。SAP97调节β1AR诱导的NO 心脏发出信号。 AIM2。SAP97保持β1AR-SAP97-NOS1信号体的完整性保留心脏功能。 AIM3。GRK5通过心力衰竭中接收器SAP97信号体的破坏。