Molecular Basis Of Transduction In Auditory Sensory Orga

听觉感觉器官转导的分子基础

• 批准号: 6814147
• 负责人: BECHARA KACHAR
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6814147
• 关键词: actin binding protein; actins; biological signal transduction; cell motility; cochlea; cochlear microphonic potentials; ear hair cell; electric field; electrostimulus; guinea pigs; immunocytochemistry; myosins; neural information processing; neural transmission; organ of Corti; sound frequency; voltage gated channel; water channel

Hearing and balance depend on sensory hair cells equipped with mechanosensitive, microvilli-like organelles, called stereocilia, that are capable of detecting displacements on a nanometer scale through mechanically gated channels located at their tips. Mammalian auditory hair cells are terminally differentiated and do not regenerate. While their stereocilia are exquisitely sensitive to mechanical vibration, orderly structured, and easily damaged by over-stimulation, they are maintained in proper working order for a lifetime. Each stereocilium is supported by a rigid paracrystalline array of several hundred parallel, uniformly polarized and regularly cross-linked actin filaments. The actin filaments are oriented such that the plus (barbed) ends are at the tips of the stereocilia and the minus (pointed) ends at the base. This organization of actin shares many construction principles with the actin formations in microvilli and filopodia yet can be up to 120?m in length. How such ordered actin formations are built, regulated, and renewed is largely unknown. We have now demonstrated that the seemingly static actin paracrystal at the core of sensory stereocilia of hair cells, undergoes continuous renewal enabled by reproducing itself at the stereocilia tips, treadmilling rearwards, and dismantling itself at the base. Treadmilling is a dynamic behavior of actin filaments that plays a crucial role in various forms of cell motility. However, little is known about the occurrence and regulation of this process in non-motile actin assemblies. We show that treadmill rates are scaled to the length of stereocilia and are modulated by local physical parameters, such as tension on the encapsulating membrane and on stereocilia links, as well as by myosins located at the tips and alongside the actin paracrystal. We propose that this regulated treadmilling dynamically shapes the functional architecture of stereocilia and plays a central role in recovery from over-stimulation. Such a dynamic view of a paracrystalline actin ensemble highlights how well organized cellular structures can maintain steady state structure, self-adjustment, and repair while undergoing continuous self-renewal.

听力和平衡取决于感觉毛细胞，这些细胞配备有机械敏感的微绒毛状细胞器（称为静纤毛），能够通过位于其尖端的机械门控通道检测纳米级的位移。哺乳动物的听毛细胞是终末分化的并且不能再生。虽然它们的静纤毛对机械振动非常敏感，结构有序，并且很容易因过度刺激而损坏，但它们终生都保持在适当的工作状态。每个静纤毛均由数百根平行、均匀极化且规则交联的肌动蛋白丝组成的刚性旁晶阵列支撑。肌动蛋白丝的方向使得正端（有倒刺的）位于静纤毛的尖端，负端（尖的）位于基部。这种肌动蛋白的组织与微绒毛和丝状伪足中的肌动蛋白结构具有许多相同的构造原理，但长度可达 120 微米。这种有序的肌动蛋白结构是如何构建、调节和更新的在很大程度上尚不清楚。我们现在已经证明，位于毛细胞感觉静纤毛核心的看似静态的肌动蛋白旁晶体，通过在静纤毛尖端自我复制、向后移动并在基部分解自身，不断进行更新。跑步是肌动蛋白丝的一种动态行为，在各种形式的细胞运动中发挥着至关重要的作用。然而，人们对非运动肌动蛋白组装中这一过程的发生和调节知之甚少。我们表明，跑步机速率与静纤毛的长度成比例，并受到局部物理参数的调节，例如封装膜和静纤毛链接上的张力，以及位于尖端和肌动蛋白旁晶体旁边的肌球蛋白。我们认为这种受调节的跑步动态地塑造了静纤毛的功能结构，并在过度刺激的恢复中发挥着核心作用。这种旁晶肌动蛋白整体的动态视图强调了组织良好的细胞结构如何在持续自我更新的同时保持稳态结构、自我调整和修复。