Spectrin-based signaling complex regulates cardiac excitability

基于血影蛋白的信号复合物调节心脏兴奋性

基本信息

批准号：
7701090
负责人：
Thomas Jeffrey Hund
金额：
$ 10.72万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7701090
关键词：
Accounting Affect Ankyrins Apoptosis Area Arrhythmia Biochemical Biogenesis Calcium/calmodulin-dependent protein kinase Cardiac Cardiac Myocytes Cell Death Cell membrane Cell physiology Cells Cessation of life Complex Coupling Data Defect Diabetes Mellitus Disease Epilepsy Functional disorder Gene Mutation Genetic Transcription Genetic Variation Heart Heart Diseases Heart failure Human Intercalated disc Ion Channel Life Link Long-Term Potentiation Maintenance Membrane Molecular Muscle Cells Neurons Nuclear Pathway interactions Patients Phase Phosphoric Monoester Hydrolases Phosphotransferases Play Principal Investigator Property Protein-Serine-Threonine Kinases Proteins Pump Regulation Research Role Scaffolding Protein Signal Transduction Spectrin Sudden Death Testing Ventricular base calmodulin-dependent protein kinase II disease phenotype genetic regulatory protein human disease in vivo innovation insight novel prevent protein complex receptor tool transcription factor voltage

项目摘要

DESCRIPTION (provided by applicant): Normal cardiac excitability depends on the coordinated biophysical activity of specific ion channels and transporters on the plasma membrane. Over the past decade, gene mutations that affect ion channel biophysical activity have been linked with fatal human arrhythmias. Recently, another class of gene mutations has been identified that alters local coupling of ion channels with cytoskeletal and regulatory proteins. It is clear that ion channel function depends on normal biophysical properties AND proper localization within specialized membrane domains. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional serine/threonine kinase with diverse cardiac roles including regulation of excitation contraction, transcription, and apoptosis. Recent findings demonstrate that local organization of CaMKII within excitable cells is essential for regulation of ion channels and receptors involved in critical cell functions such as excitation contraction coupling and long term potentiation. We have generated exciting new preliminary data that identifies a novel targeting mechanism for CaMKII to the cardiomyocyte intercalated disc. Specifically, we have identified beta lV-spectrin as a novel intercalated disc CaMKII anchoring protein that complexes CaMKII with Nav1.5, the primary voltage gated Na+ channel in heart. We have generated innovative molecular, biochemical, and mathematical tools to test our central hypothesis that a novel spectrin-based intercalated disc protein complex is critical for organizing CaMKII in context with target proteins including Nav1.5. We propose the following aims: Specific Aim 1. Determine the molecular mechanism by which beta lV-spectrin targets CaMKII to the cardiac intercalated disc. Specific Aim 2. Define the role of beta lV-spectrin in the local organization of CaMKII with Nav1,5 at the cardiac intercalated disc. Specific Aim 3. Define the role of spectrin/CaMKII signaling complex in the local regulation of primary cardiomyocyte Nav channel function, myocyte electrical activity and arrhythmogenesis.

描述（由申请人提供）：正常的心脏兴奋性取决于质膜上特定离子通道和转运蛋白的协调生物物理活性。在过去的十年中，影响离子通道生物物理活性的基因突变与致命的人体心律不齐有关。最近，已经确定了另一类的基因突变，它会改变与细胞骨架和调节蛋白的离子通道的局部耦合。显然，离子通道功能取决于正常的生物物理特性和在专用膜结构域中的适当定位。 Ca2+/钙调蛋白依赖性蛋白激酶II（CAMKII）是一种多功能丝氨酸/苏氨酸激酶，具有不同的心脏作用，包括调节激发收缩，转录和凋亡。最近的发现表明，CAMKII在可激发细胞中的局部组织对于调节关键细胞功能的离子通道和受体（例如激发收缩偶联和长期增强）至关重要。我们已经产生了令人兴奋的新初步数据，该数据确定了CAMKII的新型靶向机制，用于心肌细胞插入式椎间盘。具体而言，我们已经确定了βLV-Spectrin是一种新型的插入式椎间盘CAMKII锚定蛋白，该蛋白将CAMKII与NAV1.5（心脏中的主要电压门控Na+通道）复合在一起。我们已经生成了创新的分子，生化和数学工具，以测试我们的中心假设，即新型基于光谱的插盘蛋白质复合物对于与包括NAV1.5在内的靶蛋白的上下文中组织CAMKII至关重要。我们提出以下目的：特定目标1。确定βLV谱蛋白靶向CAMKII的分子机制。具体目的2。定义βLV光谱蛋白在CAMKII的本地组织中的作用，并在心脏插入的椎间盘上NAV1,5。特定目的3。定义频谱/camkii信号传导复合物在局部调节初级调节中的作用心肌细胞NAV通道功能，肌细胞电活动和心律失常发生。