Beta Adrenoceptor Signaling Complexes in Innervated Cardiac Myocytes

受神经支配的心肌细胞中的 β 肾上腺素受体信号传导复合物

基本信息

批准号：
8016616
负责人：
Brian K Kobilka
金额：
$ 39.84万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-15 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8016616
关键词：
Address Adrenergic Receptor Adult Affect Affinity Agonist Behavior Binding Biological Assay Biological Models Brain Cardiac Cardiac Myocytes Catecholamines Caveolae Cell Culture Techniques Cells Chimera organism Chimeric Proteins Coculture Techniques Complex Cultured Cells Cytoskeleton Data Detergents Development Disease Electrophysiology (science)Endocytic Vesicle Epinephrine Family Funding G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Goals Grant Health Heart Heart failure High Density Lipoproteins Hormone Receptor Human Genome Individual Investigation Ligand Binding Ligands Location Measurement Membrane Membrane Microdomains Methods Muscle Cells Mutation Neonatal Nerve Neurons Neurotransmitter Receptor Norepinephrine Pathogenesis Phosphorylation Physiological Play Principal Investigator Property Proteins Proto-Oncogene Proteins c-akt RNA Interference Receptor Signaling Recycling Regulation Relative (related person)Research Research Personnel Role Scaffolding Protein Signal Pathway Signal Transduction Signaling Molecule Site Site-Directed Mutagenesis Specificity Stream Structure Sudden Death Sympathetic Ganglia Synapses System Two-Hybrid System Techniques United States base cell type complement C4c design heart function in vivo interest mutant nanodisk nerve supply novel patch clamp programs protein complex protein expression protein protein interaction receptor receptor function receptor internalization research study response synaptogenesis trafficking

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to study the effect of sympathetic innervation on the formation of 21 and 22 adrenoceptor (AR) signaling complexes in the heart. We will investigate how these complexes either facilitate or restrict receptor signaling; we will identify the structural domains of the receptors that are needed for interaction with the other components of the signaling complex; and we will identify cellular proteins that define these subtype-specific signaling complexes. 21ARs and 22ARs are prototypical G protein coupled receptors (GPCRs), the largest family of hormone and neurotransmitter receptors in the human genome. These receptors are essential for the physiologic regulation of cardiac function in response to catecholamines (adrenaline and noradrenaline) released from sympathetic nerves. Recent studies suggest that 21ARs and 22ARs play distinct roles in the pathogenesis of heart failure, a growing health problem in the United States. We have developed an experimental system to study the important interface between sympathetic nerves and the heart using co-cultures of neonatal cardiac myocytes and sympathetic neurons. Our preliminary studies show that 21ARs and 22ARs have differential subcellular targeting relative to these synapses, and that signaling complexes form at the sites of synapse formation. The following aims are designed to characterize these signaling complexes. Aim 1. Determine the structural basis for subtype specific targeting and trafficking of 21ARs and 22ARs in cardiac myocytes. Aim 2. Determine the functional significance of subtype-specific localization of 21ARs and 22ARs relative to sympathetic synapses. Aim 3. Characterize protein components of the 21AR and 22AR signaling complexes in cardiac myocytes innervated by sympathetic neurons. Aim 4. Determine the functional significance of interacting proteins identified in Aim 3 on 21AR and 22AR signaling and trafficking in cardiac myocytes, and verify their existence in signaling complexes in the adult heart. The proposed studies will provide new information about how the brain regulates heart function. We will characterize the mechanism by which noradrenaline and adrenaline released from sympathetic nerves alters heart function by activation of two specific adrenergic receptors. This research will further our understanding of the development of diseases such as heart failure and sudden death.

描述（由申请人提供）：该提案的目的是研究同情神经对心脏中21和22 adrenoceptor（ar）信号复合物的形成的影响。我们将研究这些复合物如何促进或限制受体信号传导；我们将确定与信号复合物其他组件相互作用所需的受体的结构结构域；我们将确定定义这些亚型特异性信号复合物的细胞蛋白。 21AR和22AR是原型G蛋白偶联受体（GPCR），这是人类基因组中最大的激素和神经递质受体家族。这些受体对于响应儿茶酚胺（肾上腺素和去甲肾上腺素）从交感神经中释放出来的心脏功能的生理调节至关重要。最近的研究表明，21AR和22AR在心力衰竭的发病机理中起着独特的作用，这是美国日益增长的健康问题。我们已经开发了一个实验系统，以使用新生儿心肌细胞和交感神经元的共同培养来研究交感神经与心脏之间的重要接口。我们的初步研究表明，相对于这些突触，有21AR和22AR具有差异亚细胞靶向，并且在突触形成部位形成了信号传导复合物。以下目的旨在表征这些信号复合物。目标1。确定心肌细胞中21AR和22AR的亚型特异性靶向和运输的结构基础。 AIM 2。确定21AR和22AR相对于交感神经突触的亚型特异性定位的功能意义。 AIM 3。表征由交感神经元支配的心肌细胞中21AR和22AR信号复合物的蛋白质成分。 AIM 4。确定在AIM 3中在21AR和22AR信号传导和心脏肌细胞中识别的相互作用蛋白的功能意义，并验证它们在成人心脏中信号传导复合物中的存在。拟议的研究将提供有关大脑如何调节心脏功能的新信息。我们将表征从交感神经中释放出的去甲肾上腺素和肾上腺素通过激活两个特定肾上腺素受体来改变心脏功能的机制。这项研究将进一步了解心力衰竭和猝死等疾病的发展。