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

• 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
• 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

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.

新的证据表明，一氧化氮（NO）参与心脏β1肾上腺素能受体 （β 1 AR）刺激心脏功能。我们认为，支架蛋白SAP 97起着关键作用， β 1 AR-1在调节心脏β 1 AR诱导的NOS 1-NO信号级联中的作用 NOS 1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（GRK 5）促进心脏β 1 AR的磷酸化 PDZ基序和受体从SAP 97组织的信号体上解离以激活 NOS 1-NO信号转导的抑制作用，并促进心脏疾病中受体信号转导的脱敏。 我们将以下列目标来检验这些假设。目标1。SAP 97对β 1AR诱导的NO的调节作用 在心里发出信号。目标2. SAP 97保持β 1AR-SAP 97-NOS 1信号体的完整性， 保护心脏功能。目标3. GRK 5通过介导β1AR-NO信号转导促进脱敏 心力衰竭中SAP 97受体信号体的破坏。