IONIC CHANNELS OF HAIR CELLS

美国有近3000万人患有精神障碍 听力或平衡。这些人中的大多数都经历了 “感觉神经”缺陷，这主要是由精神错乱或 耳朵的感觉感受器毛细胞死亡。建议数 实验的目的是为了更好地理解 毛细胞捕捉机械刺激的转导过程- 耳蜗声，以及前庭器官的加速声- 并将它们转换成可以被解释的电响应 大脑。这些研究的长期目标是认识到听力是如何 和平衡因遗传异常、感染、耳毒性而受损 药物，创伤的声音，和衰老，从而发展理性 预防或改善听力和平衡的策略 有问题。 本申请中提出的实验涉及五个基本原则 问题。每个毛细胞都有一种适应机制，不断地 将其敏感的发束设置在最佳位置以响应 机械刺激。有人提出，适应涉及到 分子马达的活动，可能是肌球蛋白家族的一员。 第一次提出的研究意在准确地确定 由假定的马达在适应过程中产生。第二个相关的集合 的实验将探索马达对核苷酸的敏感性 有望干扰肌球蛋白样活性的类似物 分子。第三个要探讨的话题是头发的贡献 与它们所在的受体器官的机械性能有关 住下来。在这一背景下计划的研究应该表明头发 束可影响基底膜在耳蜗内的运动， 前庭中耳石膜和耳杯的运动 迷宫。在体外条件下，发束可以表现出快速的， 由机械输入触发的抽动动作。这些瞬变是 调查的第四个主题：它们是如何产生的，它们的 时间安排和对刺激的依赖，以及他们是否足够精力充沛 有助于放大耳朵中的刺激物？ 毛细胞除了对机械输入做出反应外，还有另外两种 信息处理中的重要角色：它们通过以下方式影响调整 选择行为相关性最高的频率的输入，以及 它们通过突触将信号传递给传入神经纤维。决赛 拟议研究的主题涉及两者的关键离子通道 毛细胞基底外侧突起、电压激活的钙通道 浮出水面。将努力确定这些集群是否 通道出现在发射机释放的位置。结果将会是 阐明钙离子是如何调节递质释放的，并有助于我们的 了解通过电气谐振进行频率调谐。

Nearly thirty million people in the United States suffer from impaired hearing or balance. The majority of these individuals experience "sensorineural" deficits, which largely ensue from the derangement or death of the ear's sensory receptors, the hair cells. The proposed experiments are meant to provide a better understanding of the normal transduction process by which hair cells capture mechanical stimuli - sounds in the cochlea, and accelerations in the vestibular apparatus - and transform them into electrical responses that can be interpreted by the brain. The long-term goal of the studies is to recognize how hearing and balance are impaired by genetic abnormalities, infections, ototoxic drugs, traumatic sounds, and ageing, and thus to develop rational strategies for the prevention or amelioration of hearing and balance problems. The experiments proposed in this application deal with five principal issues. Each hair cell possesses an adaptation mechanism that constantly sets its sensitive hair bundle in an optimal position to respond to mechanical stimulation. It has been proposed that adaptation involves the activity of a molecular motor, perhaps a member of the myosin family. The first proposed studies are meant to determine precisely the forces produced by the putative motor during adaptation. A second, related set of experiments will explore the sensitivity of the motor to nucleotide analogues that are expected to interfere with the activity of myosin-like molecules. A third topic to be explored is the contribution of hair bundles to the mechanical properties of the receptor organs in which they reside. The studies planned in this context should indicate whether hair bundles could influence the basilar membrane's motion in the cochlea and the movement of otolithic membranes and cupulae in the vestibular labyrinth. Under in vitro conditions, a hair bundle can display rapid, twitching motions triggered by mechanical inputs. These transients are the fourth subject of investigation: how do they arise, what is their timecourse and dependence upon stimulation, and are they energetic enough to contribute to amplification of stimuli in the ear? In addition to responding to mechanical inputs, hair cells have two other important roles in information processing: they effect tuning by selecting inputs at frequencies of greatest behavioral relevance, and they synaptically transmit signals to afferent nerve fibers. The final topic of the proposed research deals with the ion channels key to both processes, voltage-activated Ca2+ channels on a hair cell's basolateral surface. An effort will be made to determine whether clusters of these channels occur at the sites of transmitter release. The results will clarify how Ca2+ entry mediates transmitter release, and aid in our understanding of frequency tuning by electrical resonance.