IONIC CHANNELS OF HAIR CELLS

在美国有近三千万人患有 听力或平衡。 这些人中的大多数都经历过 “感觉神经”缺陷，这主要是由于神经错乱或 耳朵的感觉感受器毛细胞的死亡 拟议 实验旨在更好地了解正常情况 毛细胞捕获机械刺激的转导过程- 耳蜗的声音和前庭器官的加速度 并将其转化为电反应， 大脑 这些研究的长期目标是认识到听力 基因异常、感染、耳毒性 药物、创伤性声音和衰老，从而发展理性的 预防或改善听力和平衡的策略 问题 本申请中提出的实验涉及五个主要的 问题. 每个毛细胞都有一种适应机制， 将其敏感的发束置于最佳位置， 机械刺激 有人提出，适应包括 分子马达的活动，可能是肌球蛋白家族的一员。 第一批被提议的研究是为了精确地确定 由假定的马达在适应过程中产生。 第二个相关集 的实验将探讨敏感性的电机核苷酸 预期干扰肌球蛋白样蛋白活性的类似物 分子。 第三个要探讨的主题是头发的贡献 束的机械性能的受体器官，其中他们 居住。 在这种情况下计划的研究应该表明， 束可以影响耳蜗基底膜的运动， 前庭耳石膜和耳杯的运动 迷宫 在体外条件下，毛束可以快速， 由机械输入触发的抽搐运动。 这些瞬态是 调查的第四个主题：它们是如何产生的，它们是什么？ 时间进程和对刺激的依赖，以及他们是否足够精力充沛 来放大耳朵里的刺激 除了对机械输入做出反应外，毛细胞还有两个其他的功能。 信息处理中的重要角色：它们通过 以最大行为相关性的频率选择输入，以及 它们通过突触将信号传递到传入神经纤维。 最终 拟议的研究主题涉及离子通道的关键， 毛细胞基底外侧的电压激活的钙通道 面 将努力确定这些集群是否 通道出现在发射器释放的部位。 结果将 阐明Ca 2+进入如何介导递质释放，并帮助我们 了解通过电共振调谐频率。

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.