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Phosphorylation and gating of cardiac connexin channels

心脏连接蛋白通道的磷酸化和门控

基本信息

批准号：
9078759
负责人：
JANIS M BURT
金额：
$ 39.57万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9078759
关键词：
Accounting Acute Address Adult Affinity Alanine Anti-Arrhythmia Agents Arrhythmia Aspartate Back Behavior Beryllium Blood flow Cardiac Cardiac Myocytes Cells Cessation of life Communication Connexin 43 Connexins Coupling Cyclic AMP-Dependent Protein Kinases Data Development Disease Event Failure Global Change Goals Heart Heart Atrium Heart Diseases Heterogeneity Implantable Defibrillators Injury Intercalated disc Knowledge Lead Ligands Link Mediating Methods Modeling Molecular Muscle Cells Output Pathway interactions Pattern Periodicity Permeability Phosphorylation Physiological Property Protein Dephosphorylation Proteins Publishing Rattus Regulation Signal Transduction Site Staging Structure Tachycardia Testing Therapeutic Uses Tissues Uncertainty Ventricular Ventricular Fibrillation Ventricular Tachycardia base calmodulin-dependent protein kinase II coronary artery occlusion design gap junction channel heart function improved injured insight insulinoma intercellular communication meetings mutant novel therapeutics particle peptidomimetics preconditioning prevent public health relevance receptor sudden cardiac death targeted treatment therapy design tool voltage voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Gap junction channels (GJCh) comprise the pathway for intercellular propagation of the electrical signals responsible for coordinated activation of cardiac contraction; heterogeneity and failure of GJCh function lead to heterogeneous slowing of conduction and consequent micro- or macro-reentry circuits that set the stage for tachycardia and fibrillation in the atria and ventricles. Heterogeneity and failure of GJCh function reflect acute, phosphorylation-dependent regulation of GJCh gating and conductance. This application focuses on the GJCh gating and conductance changes that are antiarrhythmic (preconditioning) and proarrhythmic, contributing to sudden cardiac death. The long-term goals of the project are to: 1) understand the mechanisms underlying phosphorylation-dependent regulation of Cx43 GJCh and hemichannel (HCh) function, and 2) develop from that knowledge peptidomimetics that will target or induce specific functional properties of Cx43 channels that will preserve cardiac rhythmicity and prevent irreversible injury. Two key issues limit our ability to implement Cx43 based therapies. First, we do not understand the consequences of differential Cx43 phosphorylation on GJCh function. Second, the impact of heterogeneous Cx43 phosphorylation on impulse propagation in the heart is unknown. Because these issues cannot be addressed in pairs of adult ventricular myocytes (due to heterogeneity of Cx43 phosphorylation state and the large number of functioning GJChs that preclude study of gating and single channel behavior by the necessary whole-cell voltage clamp methods), we address our aims using site-mutants of Cx43 that mimic the phosphorylation state of Cx43 in normally functioning, preconditioned and injured heart. We express these Cx43 site mutants in Cx-deficient rat insulinoma cells, Cx43-deficient cardiomyocytes, and wild-type cardiomyocytes, where their gating, conductance and antiarrhythmic properties can be studied. The results of our studies will guide design and testing of function- specific, high-affinity peptidomimetics to interfere with or mimic the interactions tht underlie anti-arrhythmic GJCh and HCh function. The proposed combination of molecular, structural and functional approaches can be expected to provide new mechanistic insight on regulation of the dynamic function of Cx43 GJChs as they support the extraordinary dynamic range of cardiac function. In addition, we expect to develop Cx43- and function-specific, experimentally and therapeutically useful tools that will protect coordinated function of the heart despite ongoing disease and pharmacologic therapies.