E-C Coupling and Ca2+ Regulation atrial myocytes

E-C 耦合和 Ca2 调节心房肌细胞

• 批准号: 7275423
• 负责人: LOTHAR A BLATTER
• 金额: $ 9.92万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2008-03-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275423
• 关键词: 3-Dimensional; Adenylate Cyclase; Adrenergic Agents; Adrenergic Receptor; Affect; Arachidonic Acids; Arrhythmia; Autonomic nervous system; Behavior; Cardiac; Cardiovascular system; Cells; Characteristics; Condition; Coupled; Coupling; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Endothelin-1; Event; Frequencies; GTP-Binding Proteins; Generations; Goals; Heart Atrium; Image; Imaging Techniques; Inositol Phosphates; Laser Scanning Confocal Microscopy; Lead; Lipid Bilayers; Measurement; Mechanics; Mediating; Membrane; Methods; Morbidity - disease rate; Muscle; Muscle Cells; Nitric Oxide; Nitric Oxide Signaling Pathway; Nitric Oxide Synthase; Pattern; Phospholipases A; Play; Predisposition; Production; Protein Kinase; Pump; Receptor Signaling; Regulation; Research; Resolution; Role; Sarcoplasmic Reticulum; Signal Pathway; Signal Transduction; Site; Techniques; Testing; Tissues; Ventricular; Vesicle; Voltage-Clamp Technics; adrenergic; analog; beta-adrenergic receptor; inositol 1-phosphate; mortality; photolysis; prevent; receptor; reconstitution; spatial relationship; tool; uptake

DESCRIPTION (provided by applicant): During excitation-contraction (e-c) coupling Ca2+ release from the sarcoplasmic reticulum (SR) in atrial myocytes differs significantly from ventricular myocytes. Atrial myocytes lack transverse tubules and have two different types of SR, junctional (j-SR) and non-junctional SR (nj-SR). Ca2+ release during e-c coupling is spatially inhomogeneous. Ca2+-induced Ca2+-release (CICR) from j-SR and nj-SR is regulated by distinctly different mechanisms. In atrial myocytes IP3-dependent Ca2+ signalling modulates Ca2+ signaling during e-c coupling and cardiac contractility is regulated by the autonomic nervous system. Beta-adrenergic receptor (betaa-AR) signaling mediates symapathetic regulation of cardiac function through intracellular signaling pathways involving G-proteins, protein kinases, nitric oxide (NO) and Ca2+. Ca2+ alternans reflects the alternations of the Ca2+ transient amplitude at regular pacing frequency which results in electromechanical alternans. Atrial Ca2+ alternans are directly related to the generation of atrial arrhythmias which is a major contributor to cardiovascular morbidity and mortality. The overall goal of the proposed study is to elucidate mechanisms and signalling pathways that are relevant to normal atrial e-c coupling and their perturbations which lead to Ca2+ alternans and therefore arrhythmogenic behavior in atrial tissue. The following Specific Aims are proposed: Specific Aim #1: Determine the subcellular mechanisms by which inositol-phosphate (IP3) signaling governs Ca2+ signaling during e-c coupling. Specific Aim #2. Determine the mechanisms by which a-adrenergic signaling regulates Ca2+ release from j-SR and nj-SR during e-c coupling. Specific Aim #3. Elucidate the mechanisms through which disturbance(s) of IP3-, a-AR- and NO-dependent signaling leads to Ca2+ aiternans. To achieve these aims a multitude of experimental techniques will be used: high resolution [Ca2+]i imaging by laser scanning confocal microscopy in single atrial myocytes, whole-cell voltage clamp techniques to study membrane currents, single channel recordings through cardiac SR Ca2+ release channels reconstituted into planar lipid bilayers, subcellular photolysisof caged Ca2+ and IP3, and pharmacological manipulation of a-adrenergic regulation, IP3 signaling and Ca2+ entry, release and uptake. The proposed research will provide fundamental new information on the regulation of atrial e-c coupling and Ca2+ release under normal and altered conditions relevant to atrial arrhythmias.

描述（由申请人提供）：在兴奋 - 收缩（E-C）耦合Ca2+在心肌细胞中的肌质网（SR）释放的Ca2+释放与心肌细胞中的描述与心肌细胞中的核细胞（SR）释放。心肌细胞缺乏横向小管，并且具有两种不同类型的SR，连接（J-SR）和非官方SR（NJ-SR）。 E-C耦合期间的Ca2+释放在空间上是不均匀的。来自J-SR和NJ-SR的Ca2+诱导的Ca2+弹药（CICR）受到明显不同的机制的调节。在心肌细胞中，依赖IP3的Ca2+信号传导调节E-C耦合过程中的Ca2+信号传导和心脏收缩率在自主神经系统中调节。 β-肾上腺素能受体（betaa-ar）信号传导通过涉及G蛋白，蛋白激酶，一氧化氮（NO）和Ca2+的细胞内信号传导途径介导心脏功能的对立调节。 Ca2+替代品反映了在常规起搏频率下Ca2+瞬态幅度的交替，从而导致机电替代品。心房CA2+替代品与心房心律不齐的产生直接相关，这是导致心血管发病率和死亡率的主要因素。拟议研究的总体目标是阐明与正常心房E-E-C耦合及其扰动有关的机制和信号传导途径，这些机制导致Ca2+替代品，因此在心房组织中的心律失常行为。提出了以下具体目标： 具体目标＃1：确定肌醇 - 磷酸（IP3）信号传导在E-C耦合过程中控制CA2+信号传导的亚细胞机制。 特定目标＃2。确定A-肾上腺素能信号在E-C耦合过程中调节J-SR和NJ-SR释放Ca2+的机制。 特定目标＃3。阐明IP3-，A-AR-和NO依赖性信号的扰动导致Ca2+ Aiternans的机制。 To achieve these aims a multitude of experimental techniques will be used: high resolution [Ca2+]i imaging by laser scanning confocal microscopy in single atrial myocytes, whole-cell voltage clamp techniques to study membrane currents, single channel recordings through cardiac SR Ca2+ release channels reconstituted into planar lipid bilayers, subcellular photolysisof caged Ca2+ and IP3以及A-肾上腺素能调节，IP3信号传导和CA2+输入，释放和摄取的药理操作。 拟议的研究将提供有关在正常和改变与心房心律失常有关的正常和改变的条件下对心房E-C耦合调节和Ca2+释放的基本新信息。