Molecular Basis of Transduction in Auditory Sensory Orga

听觉感觉器官转导的分子基础

• 批准号: 7130143
• 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/7130143
• 关键词: biological signal transduction; biomechanics; calcium transporting ATPase; cochlea; ear hair cell; membrane proteins; organ of Corti; protein isoforms; protein transport; sensory signal detection

Stereocilia, are specialized actin protrusions on the surface of the sensory cells of the inner ear where the key step in the process of mechanical to electrical transduction takes place. In each cell, stereocilia are organized in bundles of precisely adjusted graded lengths forming characteristic staircase patterns. The pattern of organization and dimensions of the stereocilia are matched to specific stimulus frequency selectivity. Stereocilia are extraordinarily mechanically sensitive and can be easily disrupted by over-stimulation. An important question that follows is: How they can maintain their ordered structure, be so sensitive, and function continuously for a lifetime? The answer may be in the existence of a rapid constitutive turnover and recycling of the stereocilia molecular components. We have previously shown that the cytoskeletal core of sensory stereocilia undergoes continuous rapid renewal. However, the renewal of stereocilia membrane components remains poorly understood. We studied the spatial distribution, mobility, and trafficking of plasma membrane Ca2+-ATPase isoform 2 (PMCA2) as a model system to evaluate the extent and the mechanisms for renewal of stereocilia membrane proteins. PMCA2 is localized along the entire stereocilia membrane where it is highly abundant and uniformly distributed. We measured the rate of internalization of constitutively expressed PMCA2, we analyzed the recycling and mobility of GFP tagged PMCA2, and characterized the membrane traffic machinery present at the apical region of the hair cells. Our results show the presence of a large mobile fraction of PMCA2 with a very high lateral mobility. This mobile pool of PMCA2 mediates the uniform distribution of PMCA2 between neighboring stereocilia, as well as the exchanges between the stereocilia and the rapid internalization and delivery that takes place at the periphery of the apical cell surface. Based on our results we argue that PMCA2 and likely other stereocilia membrane proteins can turnover at fast rates, matching the previously described rapid turnover of the actin core components further demonstrating that these organelles undergo rapid renewal and continuous dynamic regulation.

静纤毛是内耳感觉细胞表面上的特化肌动蛋白突起，在机械到电转换过程中的关键步骤发生。在每个细胞中，静纤毛被组织成束的精确调整梯度长度形成特征的楼梯图案。静纤毛的组织模式和尺寸与特定的刺激频率选择性相匹配。静纤毛对机械非常敏感，并且很容易被过度刺激破坏。随之而来的一个重要问题是：它们如何能够保持其有序的结构，如此敏感，并在一生中持续发挥作用？答案可能是静纤毛分子组分的快速组成性周转和再循环。我们以前已经表明，感觉静纤毛的细胞骨架核心经历连续快速更新。然而，静纤毛膜组件的更新仍然知之甚少。我们研究了空间分布，流动性和运输的质膜Ca 2 +-ATP酶异构体2（PMCA 2）作为一个模型系统，以评估的程度和更新的静纤毛膜蛋白的机制。PMCA 2沿着整个静纤毛膜定位，在那里它是高度丰富和均匀分布的。我们测量了组成型表达的PMCA 2的内化速率，我们分析了GFP标记的PMCA 2的回收和流动性，并表征了毛细胞顶端区域存在的膜交通机制。我们的研究结果表明，存在一个大的移动的部分的PMCA 2具有非常高的横向流动性。PMCA 2的这种移动的池介导PMCA 2在相邻静纤毛之间的均匀分布，以及静纤毛之间的交换和在顶端细胞表面周围发生的快速内化和递送。基于我们的研究结果，我们认为PMCA 2和其他可能的静纤毛膜蛋白可以快速周转，与先前描述的肌动蛋白核心组分的快速周转相匹配，进一步证明这些细胞器经历快速更新和持续的动态调节。