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：
8322779
负责人：
Thomas Jeffrey Hund
金额：
$ 24.9万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8322779
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 Cytoskeletal Proteins 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 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类心律失常有关。最近，已经鉴定出另一类基因突变，它们改变了离子通道与细胞骨架和调节蛋白的局部耦合。很明显，离子通道功能取决于正常的生物物理特性和专门膜域内的正确定位。 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，具有多种心脏作用，包括调节兴奋性收缩、转录和细胞凋亡。最近的研究结果表明，可兴奋细胞内 CaMKII 的局部组织对于调节涉及关键细胞功能（例如兴奋收缩耦合和长时程增强）的离子通道和受体至关重要。我们已经生成了令人兴奋的新初步数据，确定了 CaMKII 靶向心肌细胞闰盘的新靶向机制。具体来说，我们已经确定 β IV-血影蛋白是一种新型嵌入盘 CaMKII 锚定蛋白，可将 CaMKII 与 Nav1.5（心脏中的主要电压门控 Na+ 通道）复合。我们已经开发出创新的分子、生化和数学工具来测试我们的中心假设，即一种新型的基于血影蛋白的闰盘蛋白复合物对于组织 CaMKII 与包括 Nav1.5 在内的靶蛋白相关。我们提出以下目标：具体目标 1. 确定 β IV-血影蛋白将 CaMKII 靶向心脏闰盘的分子机制。具体目标 2. 定义 β IV-血影蛋白在心脏闰盘处 CaMKII 与 Nav1,5 的局部组织中的作用。具体目标 3. 定义血影蛋白/CaMKII 信号复合物在原发性局部调节中的作用心肌细胞 Nav 通道功能、心肌细胞电活动和心律失常发生。