Decoding the enigma of cardiac amplification

摘要 已建立的肌肉收缩的“滑动细丝理论”，虽然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分子层的变化 肌节缩短过程中的花丝。为了调和这一无法解释的现象，我们团队花了最后一段时间 十年来一直在努力解决这个难题，最近发现了一种机械放大器，一种非机械放大器 传统的运动蛋白Prestin(SLC26A5)及其寡聚体SLC26a6在心肌细胞中作为一种 肌肉放大器。Prestin是溶质载体基因家族的一员。我们假设压力作用于 作为一个“弹簧”来放大肌动蛋白-肌球蛋白的力量产生，并解释了肌肉的非线性特性 收缩。具体来说，我们假设prestin在心肌细胞中表达，并作为一种非 常规马达。Prestin在SLC26蛋白家族中是不同的，因为它在 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 一种高效的转运蛋白，可以在细胞内产生氯离子微域，从而发挥Prestin的正常功能。使用直接 电生理测量表明，prestin确实是一种弱阴离子转运蛋白 使用SLC26a6。为了有效地发挥作用，Prestin需要一个强大的阴离子交换剂来实现其最佳功能。因此， 我们假设prestin需要一个“团队成员”，slc26a6，来形成异构体蛋白来执行不同的功能。 在心肌细胞中的功能。总体而言，我们的发现极大地挑战了该领域当前的范式和 如果没有看似不同的学科之间的密切合作 神经科学、心血管和生物医学工程研究单位。 1

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