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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：
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

抽象的既定的肌肉收缩“滑动丝理论”，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期间的丝。为了解决这个无法解释的现象，我们小组花了最后的时间十年来一直在努力应对这一困境，最近发现了一种机械放大器，一种非心肌细胞中的传统运动蛋白 prestin (Slc26a5) 及其寡聚物 Slc26a6，作为肌肉放大器。 Prestin 是溶质载体 (SLC) 基因家族的成员。我们假设 prestin 起作用作为“弹簧”来放大肌动蛋白-肌球蛋白力的产生并解释肌肉的非线性特性收缩。具体来说，我们假设 prestin 在心肌细胞中表达，并作为非传统电机。 Prestin 在 SLC26 蛋白家族中是独特的，因为它的分子运动功能与其他成员的阴离子转运功能形成对比。我们进一步假设 Slc26a6 是必需的一种有效的转运蛋白，可产生细胞内 Cl- 微结构域，以实现 prestin 的正常功能。使用直接通过电生理测量，我们证明 prestin 确实是一种较弱的阴离子转运蛋白与Slc26a6。为了有效发挥作用，prestin 需要强阴离子交换剂才能发挥最佳功能。因此，我们假设 prestin 需要一个“团队成员”Slc26a6，来形成异聚蛋白来执行不同的功能在心肌细胞中发挥作用。总的来说，我们的发现极大地挑战了该领域当前的范式除非看似不同的学科之间进行密切合作，否则这一目标是不可能实现的。神经科学、心血管和生物医学工程研究单位。 1