Decoding the enigma of cardiac amplification

解开心脏放大之谜

基本信息

批准号：
9902512
负责人：
Nipavan Chiamvimonvat
金额：
$ 59.4万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902512
关键词：
Actins Amplifiers Anions Binding Proteins Biological Assay Biomedical Engineering Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cells Cessation of life Clinical Co-Immunoprecipitations Collaborations Confocal Microscopy Discipline Echocardiography Electric Capacitance Electrophysiology (science)Elements Etiology Family member Filament Gene Family Generations Heart Heart Atrium Heart failure Human Image Immunoelectron Microscopy Immunofluorescence Immunologic In Vitro Inner Hair Cells Integral Membrane Protein Knowledge Labyrinth Lipid Bilayers Malignant Neoplasms Measurement Mechanics Mediating Microscopy Molecular Molecular Motors Motivation Motor Mus Muscle Muscle Cells Muscle Contraction Mutant Strains Mice Myosin ATPase Neurosciences Outer Hair Cells Patients Physiological Property Protein Family Proteins Quantitative Reverse Transcriptase PCR Relaxation Research Personnel Resolution Reverse Transcriptase Polymerase Chain Reaction Rodent Role Sarcolemma Sarcomeres Sigma Factor Slide Testing Therapeutic Transcript United States Ventricular Western Blotting confocal imaging connectin fluorescence imaging heart function improved in vivo interdisciplinary approach live cell imaging member mortality mouse model protein protein interaction rat Pres protein sensor solute sound stem sulfate transporter theories

项目摘要

Abstract The established “sliding-filament theory” of muscle contraction, while it is adequate to explain actin-myosin force generation, does not suffice to account for changes in membrane lipid bilayer parallel to the sliding filament during sarcomere shortening. To reconcile this unexplained phenomenon, our group has spent the last decade trying to contend with this dilemma and have recently identified a mechanical amplifier, a non- conventional motor protein, prestin (Slc26a5) and its oligomer Slc26a6 in cardiac myocytes, serving as a muscle amplifier. Prestin is a member of the solute carrier (SLC) gene family. We hypothesize that prestin acts as a “spring” to amplify actin-myosin force generation and accounts for the non-linear properties of muscle contraction. Specifically, we hypothesize that prestin is expressed in cardiac myocytes and serves as a non- conventional motor. Prestin is distinct in SLC26 family of proteins because of its molecular motor function in contrast to the anion transport functions of other members. We further hypothesize that Slc26a6 is required as an efficient transporter to create intracellular Cl- microdomain for the proper function of prestin. Using direct electrophysiological measurements, we demonstrate that prestin is indeed, a weak anion transporter compared with Slc26a6. To function effectively, prestin requires a strong anion exchanger for its optimal function. Thus, we hypothesize that prestin requires a “team player”, Slc26a6, to form heteromeric proteins to perform distinct functions in cardiac myocytes. Collectively, our findings greatly challenge the current paradigm in the field and would not have been realized except for a close collaboration among seemingly disparate disciplines in neuroscience, cardiovascular, and biomedical engineering investigative units. 1

抽象的肌肉收缩的既定“滑丝理论”，而足以解释肌动蛋白肌球蛋白力产生，不足以说明平行于滑动的膜脂质双层的变化肌节缩短期间的细丝。为了调和这种无法解释的现象，我们的小组花了最后一个十年试图遏制这种困境，并最近确定了机械放大器，一种非 - 常规的运动蛋白，Prestin（SLC26A5）及其在心肌细胞中的低聚物SLC26A6，作为一个肌肉放大器。 Prestin是可溶性载体（SLC）基因家族的成员。我们假设普雷斯汀行动作为放大肌动蛋白肌球蛋白力产生并说明肌肉非线性特性的“弹簧” 提议，我们假设普雷斯汀在心肌细胞中表达常规电动机。 Prestin在SLC26蛋白质家族中与众不同，因为其分子运动功能在与其他成员的阴离子运输功能形成对比。我们进一步假设需要SLC26A6为有效的转运蛋白可创建细胞内cl-微区域，以适当的Prestin功能。使用直接电生理测量值，我们证明了普雷斯汀确实是一个弱阴离子转运蛋白与SLC26A6。为了有效地功能，Prestin需要强大的阴离子交换器才能达到其最佳功能。那，我们假设Prestin需要一个“团队玩家” SLC26A6才能形成异源蛋白来执行不同的蛋白质在心肌细胞中起作用。总体而言，我们的发现极大地挑战了该领域的当前范式除了在看似不同的学科之间进行密切合作，无法实现神经科学，心血管和生物医学工程调查单元。 1