BETA1 AND BETA2 ADRENOCEPTOR SIGNALING IN CARDIAC MYOCYTE

心肌细胞中的 Beta1 和 Beta2 肾上腺素信号传导

• 批准号: 7350161
• 负责人: YANG K XIANG
• 金额: $ 29.25万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7350161
• 关键词: Address; Adenoviruses; Adrenal Glands; Adrenergic Receptor; Agonist; Animals; Apoptosis; Behavior; Binding; Biochemical; Biological Models; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular Physiology; Catecholamines; Cells; Chronic; Complex; Coupling; Cyclic AMP-Dependent Protein Kinases; Degradation Pathway; Drug Design; Epinephrine; Fright; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Goals; Heart; Heart Rate; Heart failure; Kinetics; Knock-out; Knockout Mice; Life; Ligand Binding; Ligands; Long-Term Effects; Measurement; Modification; Molecular Conformation; Mus; Muscle Cells; Neonatal; Norepinephrine; Phosphorylation; Property; Proteins; Rate; Receptor Signaling; Regulation; Relative (related person); Role; Signal Pathway; Signal Transduction; Signaling Molecule; Structure; Sympathetic Nervous System; Ubiquitination; Yang; cell type; cellular imaging; clinical application; clinically relevant; density; desensitization; in vivo; mutant; receptor; receptor recycling; response; trafficking

3 Adrenoceptors (pARs) signaling is finely regulated to control cardiovascular function in response to sympathetic nervous system input (norepinephrine) and to adrenaline (epinephrine) from the adrenal gland. In animal hearts, two highly homologous pARs (P1AR and P2AR) are stimulated by catecholamines to enhance contractility and heart rate. Chronic stimulation of cardiac (3ARs by elevated circulating catecholamines as well as decreased cardiac (31AR density is clinically associated with heart failure. The primary functions attributed to GPCRs are ligand binding and G-protein coupling. However, the specific and diversified functional properties of GPCRs in vivo involve kinetic receptor conformational changes for binding different partners in signaling complexes, and the localization of receptor signaling complexes in cell type- specific manner. We hypothesize that norepinephrine and epinephrine can activate distinct signaling pathways for both (31AR and (32AR in cardiac myocyte. We have chosen the neonatal cardiac myocyte isolated from the PAR gene deficiency mice as a model system to study the functional roles of ligand- receptor interactions in differentiated cells. The goals of this proposal are (1) to characterize (31 AR and |32AR subtype-specific signaling by different agonists in neonatal myocytes, (2) define the cellular and biochemical properties of (31 AR and P2AR under norepinephrine and epinephrine stimulation in cardiac myocytes, (3) to characterize the subcellular distribution of (31ARand (32AR, and other signaling molecules under norepinephrine and epinephrine stimulation in cardiac myocyte, (4) to identify receptor interaction domains and their targeted proteins, and to characterize the receptor signaling complex formation and stability upon agonist stimulation. A better understanding of agonist-induced PAR conformationchange for the organization of signaling complexes may facilitate new drug designs and suggest new clinical applications in treating various cardiovascular diseases.

3肾上腺素受体(PARs)信号被精细调节以控制心血管功能 交感神经系统的输入(去甲肾上腺素)和肾上腺的肾上腺素(肾上腺素)。 在动物心脏中，儿茶酚胺刺激两个高度同源的Pars(P1AR和P2AR)以 增强收缩能力和心率。慢性心脏刺激(3ARs)，通过升高循环 儿茶酚胺和心脏(31AR密度降低)在临床上与心力衰竭有关。这个 GPCRs的主要功能是配体结合和G蛋白偶联。然而，具体的和 GPCRs在体内的多种功能特性涉及结合受体的动态构象变化 信号复合体中的不同伙伴，以及受体信号复合体在细胞类型中的定位- 具体的方式。我们假设去甲肾上腺素和肾上腺素可以激活不同的信号。 (31AR和(32AR)在心肌细胞中的作用途径。我们选择了新生心肌细胞 从PAR基因缺陷小鼠分离作为模型系统，研究配体-2的功能作用 分化细胞中的受体相互作用。本提案的目标是(1)描述(31 AR和 新生儿心肌细胞中不同激动剂的32AR亚型特异性信号转导，(2)定义细胞和 心脏去甲肾上腺素和肾上腺素刺激下(31AR和P2AR)的生化特性 肌细胞，(3)表征(31AR和(32AR)及其他信号分子的亚细胞分布 在去甲肾上腺素和肾上腺素刺激下的心肌细胞，(4)识别受体相互作用 结构域及其靶蛋白，并表征受体信号复合体的形成和 激动剂刺激下的稳定性。更好地理解激动剂诱导的PAR构象变化 信号复合体的组织可以促进新药设计和建议新的临床 在治疗各种心血管疾病中的应用。