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Decoding the enigma of cardiac amplification

解开心脏放大之谜

基本信息

批准号：
9323044
负责人：
Nipavan Chiamvimonvat
金额：
$ 48.83万
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 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9323044
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 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 connectin fluorescence imaging 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

摘要已建立的肌肉收缩的“滑丝理论”，而它足以解释肌动蛋白-肌球蛋白力的产生，不足以解释平行于滑动的膜脂双层的变化肌节缩短时的肌丝。为了调和这一无法解释的现象，我们的团队花了最后一段时间，十年来试图与这种困境作斗争，最近确定了一种机械放大器，一种非心肌细胞中的常规马达蛋白，普雷斯廷（Slc 26 a5）及其寡聚体Slc 26 a6，作为心肌细胞中的一种肌肉放大器普雷斯廷是溶质载体（solute carrier，SLC）基因家族的一员。我们假设普雷斯廷作为一个“弹簧”，以放大肌动蛋白-肌球蛋白力的产生，并解释肌肉的非线性特性收缩。具体地说，我们假设普雷斯廷在心肌细胞中表达，并作为一种非- 传统电机普雷斯廷在蛋白质的SLC 26家族中是独特的，因为其在细胞内的分子马达功能。与其他成员的阴离子转运功能形成鲜明对比。我们进一步假设Slc 26 a6是必需的，为普雷斯廷的正常功能产生细胞内Cl-微结构域的有效转运蛋白。使用直接电生理测量，我们证明，普雷斯廷确实是一个弱阴离子转运体相比，关于Slc 26 a6为了有效地发挥作用，普雷斯廷需要强阴离子交换剂以实现其最佳功能。因此，在本发明中，我们假设普雷斯廷需要一个“团队成员”Slc 26 a6来形成异聚体蛋白，以执行不同的功能。在心肌细胞中起作用。总的来说，我们的发现极大地挑战了该领域的现有范式，如果不是在看似不同的学科之间进行密切合作，神经科学、心血管和生物医学工程研究单位。 1