Identifying the physical stimuli for activation and sensitization of Piezo mechanosensitive ion channels

 描述(由申请人提供)：机械敏感离子通道对于机械转导或将机械力转换为生物相关信号是必不可少的。最近，两个新的跨膜蛋白Piezo1和Piezo2被鉴定为脊椎动物机械敏感离子通道的成孔亚基。Piezos在不同的机械刺激下开放，导致阳离子流入；这反过来又导致细胞膜去极化和下游通路的启动。Piezos是默克尔细胞对光接触的反应和血管系统正常发育所必需的。此外，Piezo离子通道功能的破坏与几种人类疾病有关，并可能导致与炎症途径相关的痛觉过敏。Piezos与其他离子通道几乎没有同源性，尽管它们在正常生理中发挥着重要作用，但它们的许多功能仍不清楚。特别是，导致孔打开的膜和/或通道上的比力尚未确定。本文提出的实验旨在阐明Piezos的激活机制。具体地说，他们测试了膜曲率和/或张力作为Piezos感觉到的潜在物理刺激的作用。此外，这些实验还将检验炎性化合物以及自然失活调节Piezos对给定刺激的敏感性的机制。识别激活Piezos的Physica刺激及其调节方式将有助于进一步了解这些蛋白质在异常生理中的作用，并为药物靶向提供信息。

 DESCRIPTION (provided by applicant): Mechanosensitive ion channels are essential for mechanotransduction, or the conversion of mechanical force into a biologically relevant signal. Recently, two novel membrane-spanning proteins, Piezo1 and Piezo2, were identified as pore-forming subunits of a vertebrate mechanosensitive ion channel. Piezos open in response to diverse mechanical stimuli, leading to an influx of cations; this in turn leads to depolarization o the cell membrane and initiation of downstream pathways. Piezos are required for responses to light touch in Merkel cells and normal development of the vascular system. Moreover, disruption of Piezo ion channel function is implicated in several human diseases and may contribute to hyperalgesia associated with inflammatory pathways. Piezos share little homology with other ion channels, and despite their important role in normal physiology many aspects of their function remain unknown. In particular, the specific forces on the membrane and/or channel that lead to pore opening have yet to be established. The experiments proposed here are designed to elucidate the activation mechanism of Piezos. Specifically, they test the contributions of membrane curvature and/or tension as potential physical stimuli that Piezos sense. Additionally, these experiments will examine the mechanisms by which inflammatory compounds as well as native inactivation modulate the sensitivity of Piezos to a given stimulus. Identifying the physica stimulus that activates Piezos and the means by which it can be modulated will help further the understanding of the role of these proteins in abnormal physiology, as well as inform pharmacological targeting.