Regulation of Adenylyl Cyclase Signaling Pathways

腺苷酸环化酶信号通路的调节

• 批准号: 8579094
• 负责人: Carmen W. Dessauer
• 金额: $ 32.18万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579094
• 关键词: A kinase anchoring protein; Accounting; Action Potentials; Address; Adenylate Cyclase; Adenylyl Cyclase 9; Adrenergic Agents; Adult; Agonist; Arrhythmia; Binding; Biochemical; Biological Assay; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cavia; Cells; Chronic; Complex; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Dilatation - action; Dinoprostone; Echocardiography; Electrocardiogram; Enzymes; Event; Exercise; Fluorescence Resonance Energy Transfer; Forskolin; Gene Mutation; Growth; Heart; Heart Diseases; Heart Rate; Heart failure; Heterotrimeric GTP-Binding Proteins; Hormonal; Human; Hypertrophy; Image; Isoproterenol; Knock-out; Lead; Long QT Syndrome; Macromolecular Complexes; Measures; Mechanics; Membrane; Modeling; Mus; Muscle Cells; Mutation; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Play; Production; Protein Binding; Protein Isoforms; Protein Kinase; Proteins; Regulation; Research; Role; Scaffolding Protein; Seizures; Signal Pathway; Signal Transduction; Specificity; Spinal Ganglia; Stress; Sudden Death; Syncope; TRPV1 gene; Techniques; Therapeutic Intervention; Time; Transgenic Mice; Ventricular Dysfunction; adenylyl cyclase 6; adrenergic; base; cellular targeting; chronotropic; fighting; heart function; heart rhythm; hormone regulation; mouse model; novel; plectin; protein complex; public health relevance; response; scaffold

DESCRIPTION (provided by applicant): The cAMP pathway has key physiological effects on heart function and is essential for the chronotropic, inotropic and lusitropic effects during the 'fight-or-flight' response. However, chronic activation of the cAMP pathway induces hypertrophic growth and ventricular dysfunction, which ultimately leads to the development of chamber dilatation and heart failure. Despite the description of a number of alterations in the cAMP pathway during hypertrophy and heart failure, the exact mechanisms accounting for the cardiotoxicity of this pathway are not fully understood. Much research has been dedicated to understanding the roles in heart for types 5 and 6 adenylyl cyclase (AC), the enzymes that synthesize cAMP. However roles for additional ACs expressed in cardiac myocytes have been largely overlooked. We have recently shown that type 9 AC is not only expressed in adult mouse cardiomyocytes, but is the only AC isoform to associate with the Yotiao- IKs complex in both transgenic mouse models and guinea pig heart. Sympathetic responses increase cAMP signaling which increases IKs current and shortening of the action potential duration to allow sufficient diastolic intervals in the face of increased heart rate. Mutations that disrupt interactons between the IKs channel subunit (KCNQ1) and the scaffolding protein Yotiao give rise to Long-QT syndrome. We have provided significant evidence that adenylyl cyclase (AC) is an integral part of signaling scaffolds known as A-kinase anchoring proteins (AKAPs) that coordinate events both upstream and downstream of cAMP production. We hypothesize that AC9 plays a key role in cAMP regulation of cardiac function and IKs regulation via interactions with Yotiao and possibly additional AKAPs. Specific Aims will 1) examine the enzymatic regulation of AC9 and real-time production of cAMP in cardiac myocytes, 2) identify and characterize AC9 complexes in cardiac myocytes, and 3) examine the functional roles of AC9 in heart.

描述（由申请人提供）：营地通道对心脏功能具有关键的生理影响，对于“战斗或飞行”反应期间的表年度，肌力和肌肉效应至关重要。然而，CAMP途径的慢性激活会诱导肥厚性生长和心室功能障碍，最终导致腔室扩张和心力衰竭的发展。尽管描述了肥大和心力衰竭期间营地途径的许多变化，但尚未完全了解解决该途径心脏毒性的确切机制。许多研究都致力于理解5型和6型腺苷酸环化酶（AC）的角色，即合成cAMP的酶。然而，在心肌细胞中表达的其他AC的角色在很大程度上被忽略了。我们最近表明，9型AC不仅在成年小鼠心肌细胞中表达，而且是转基因小鼠模型和豚鼠心脏中唯一与Yotiao-iks复合物相关的AC同工型。交感反应会增加cAMP信号传导，从而增加IKS的电流并缩短动作势持续时间，以允许面对心率增加的足够的舒张期间。破坏IKS通道亚基（KCNQ1）和脚手架蛋白Yotiao之间相互作用的突变会引起长QT综合征。我们提供了重要的证据表明，腺苷酸环化酶（AC）是信号支架的组成部分，称为A-激酶锚定蛋白（AKAP），它们协调cAMP生产的上游和下游事件。我们假设AC9通过与Yotiao的相互作用以及可能的其他AKAP在心脏功能和IKS调节中起关键作用。具体目的是1）检查心肌细胞中AC9的酶调节和CAMP的实时产生，2）识别和表征心肌细胞中AC9复合物，以及3）检查心脏中AC9的功能作用。