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The role of NompC (=TRPN1) for mechanotransducer gating and adaptation in the Drosophila ear

NompC (=TRPN1) 在果蝇耳朵机械传感器门控和适应中的作用

基本信息

批准号：
BB/G004455/1
负责人：
Joerg Albert
金额：
$ 58.02万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2009
资助国家：
英国
起止时间：
2009 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FG004455%2F1
关键词：
role NompC =TRPN1 mechanotransducer gating

项目摘要

At the heart of all sensation lies a common process: The opening or closing (called the gating) of dedicated ion channels in the membranes of sensory cells. These so-called sensory transducer channels convert external stimulus energy- such as the mechanical energy contained in a sound wave- into an electrical current that flows through the sensory cell's membrane. In the case of the classical mechanical senses, i.e. the senses of touch, hearing and balance, these mechano-transducer channels are deemed to be gated in the most direct way possible, namely by the stimulus forces themselves. This direct mode of activation implies that the transducers must somehow be mechanically coupled to specialized stimulus receiver structures, such as our ear drums or the antennal sound receivers of fruit flies, for example. Somewhat ironically, however, the astonishing simplicity of their mode of activation appears to have greatly complicated the molecular identification of true mechano-transducer channels to this day. Recently, it was demonstrated that mechano-transduction in the sensory cells of the fruit-fly (Drosophila) ear, relies on mechano-transducer channels that operate according to the same biophysical principles as those in the inner ears of vertebrates. Fortunately, in Drosophila, the function of these transducer channels can be assessed in vivo, in the ears of intact flies. Given the enormous genetic tractability of the fruit fly, along with the availability of a multitude of mechano-sensory mutants, the Drosophila ear therefore constitutes an ideal system in which to probe the specific roles of identified proteins in the process of mechano-sensation, particularly their contributions to mechano-transduction. This proposal will initiate the molecular dissection of mechano-transducer function in the Drosophila ear by specifically assessing the role of an ion channel called NompC. The NompC channel, which reportedly serves mechanosensory functions in the ears of both vertebrates and invertebrates, is presently the best candidate for a true, auditory mechano-transducer channel. A common feature of mechano-transducers in the ears of both fruit flies and vertebrates seems to be their ability to adapt to a maintained stimulus: in vertebrate hair cells this adaptation is mediated by specialized adaptation motors which act to release tension from those elements that couple forces to the transducer channels, thus allowing for the channels to close despite the presence of the stimulus. Most remarkably, the adaptation of transducer channels in the Drosophila ear appears to operate in the same way as in vertebrates. Several lines of evidence have suggested an involvement of NompC in the process of mechano-transduction or mechano-transducer adaptation in Drosophila but more direct evidence remains outstanding. By using biophysical, transgenetic and modelling approaches, I will investigate the specific contribution of NompC to mechano-transduction and/or adaptation in the Drosophila ear. Despite the fact that the NompC channel, though present in the ears of non-mammalian vertebrates, seems to be absent from the ears of mammals, the study proposed here will also provide for a better understanding of our own ears' workings. Studies in non-mammalian vertebrates, such as turtles and frogs have provided much insight into fundamental mechanisms of auditory function that also apply in mammals, This study in the fruit fly is likewise expected to make a significant contribution to our molecular understanding of how ears translate the mechanical forces provided by sound into electrical signals which can be processed further on in the brain.

所有感觉的核心都有一个共同的过程：感觉细胞膜上专用离子通道的打开或关闭(称为门控)。这些所谓的感觉传感器通道将外部刺激能量--如声波中包含的机械能--转化为流经感觉细胞膜的电流。对于经典的机械感觉，即触觉、听觉和平衡感觉，这些机械传感器通道被认为是以最直接的方式控制的，即由刺激力本身控制。这种直接的激活模式意味着，传感器必须以某种方式机械地连接到专门的刺激接收器结构，例如我们的耳膜或果蝇的天线声音接收器。然而，有些讽刺的是，它们的激活模式惊人地简单，似乎使至今真正的机械转导通道的分子鉴定变得非常复杂。最近的研究表明，果蝇耳部感觉细胞的机械转导依赖于机械转导通道，机械转导通道的工作原理与脊椎动物的内耳相同。幸运的是，在果蝇体内，这些转导通道的功能可以在正常果蝇的耳朵中进行体内评估。考虑到果蝇巨大的遗传易感性，以及大量机械感觉突变体的可获得性，果蝇耳朵因此构成了一个理想的系统，在其中可以探索识别的蛋白质在机械感觉过程中的特定作用，特别是它们对机械感觉转导的贡献。这项提议将通过专门评估称为NompC的离子通道的作用，启动对果蝇耳朵中机械转导功能的分子解剖。据报道，NompC通道在脊椎动物和无脊椎动物的耳朵中都具有机械感觉功能，目前是真正的听觉机械换能器通道的最佳候选者。果蝇和脊椎动物耳朵中机械传感器的一个共同特征似乎是他们对持续刺激的适应能力：在脊椎动物毛细胞中，这种适应是由专门的适应电机介导的，这些电机从那些将力耦合到传感器通道的元件中释放张力，从而允许通道在存在刺激的情况下关闭。最值得注意的是，果蝇耳朵中的转导通道的适应似乎与脊椎动物的操作方式相同。一些证据表明，NompC参与了果蝇的机械转导或机械转导适应过程，但更直接的证据仍然突出。通过生物物理、转基因和建模的方法，我将研究NompC在果蝇耳朵的机械转导和/或适应中的具体贡献。尽管NompC通道存在于非哺乳类脊椎动物的耳朵中，但哺乳动物的耳朵中似乎没有NompC通道，但这里提出的这项研究也将提供更好的了解我们自己耳朵的工作原理。对非哺乳动物脊椎动物，如海龟和青蛙的研究提供了许多关于听觉功能的基本机制的见解，也适用于哺乳动物，这项在果蝇上的研究同样有望为我们理解耳朵如何将声音提供的机械力转化为电信号，并在大脑中进一步处理做出重大贡献。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Active Process Mediates Species-Specific Tuning of Drosophila Ears

DOI：
10.1016/j.cub.2011.03.001
发表时间：
2011-04-26
期刊：
CURRENT BIOLOGY
影响因子：
9.2
作者：
Riabinina, Olena;Dai, Mingjie;Albert, Joerg T.
通讯作者：
Albert, Joerg T.

A doublecortin containing microtubule-associated protein is implicated in mechanotransduction in Drosophila sensory cilia.

DOI：
10.1038/ncomms1007
发表时间：
2010-04-12
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Bechstedt, S.;Albert, J. T.;Kreil, D. P.;Mueller-Reichert, T.;Goepfert, M. C.;Howard, J.
通讯作者：
Howard, J.

Turnover and activity-dependent transcriptional control of NompC in the Drosophila ear.