Structure Function of Mechanically Activated Ion Channel

描述（由申请人提供）：对于触觉/疼痛感和听觉，已表征了响应于机械力而直接激活的阳离子通道。此外，包括血管平滑肌细胞在内的许多其他细胞类型表达这种机械激活（MA）阳离子电流，并且机械转导涉及各种生物过程和疾病。然而，值得注意的是，脊椎动物中这些离子通道的身份仍然未知。我们最近确定了MA阳离子通道组件在脊椎动物命名为Piezo 1和Piezo 2。在多种哺乳动物细胞系中表达Piezos诱导大的MA阳离子电流。Piezos在涉及机械转导的多种组织中表达。Piezo 1和Piezo 2含有超过24个推定的跨膜结构域，但不类似于已知的离子通道或其他蛋白质类。关于这些蛋白质的结构仍有许多重要的悬而未决的问题。在这里，我们假设Piezo 1寡聚化形成机械激活离子通道的含孔亚基。 公共卫生相关性：机械传导影响多种生物系统和疾病，并且与听力和耳聋、炎性疼痛状态、心血管疾病、骨质疏松症有关。事实上，许多细胞使用机械敏感性来协调细胞和组织生长，这些机制的失败可能导致癌症和其他病理学。因此，对机械感觉的分子理解是重要的，并且与各种医学适应症相关。

DESCRIPTION (provided by applicant): For sense of touch/pain and hearing, cation channels that are directly activated in response to mechanical forces have been characterized. In addition, many other cell types including vascular smooth muscle cells express such mechanically-activated (MA) cationic currents, and mechanotransduction is implicated in various biological processes and diseases. Remarkably, however, the identity of these ion channels in vertebrates has remained unknown. We recently identified MA cation channel components in vertebrates named Piezo1 and Piezo2. Expressing Piezos in a variety of mammalian cell lines induce large MA cationic currents. Piezos are expressed in a variety of tissues implicated in mechanotransduction. Piezo1 and Piezo2 contain over 24 putative transmembrane domains but do not resemble known ion channels or other protein classes. Many important open questions remain about the structure of these proteins. Here, we hypothesize that Piezo1 oligomerizes to form pore-containing subunits of mechanically-activated ion channels. PUBLIC HEALTH RELEVANCE: Mechanotransduction impacts a variety of biological systems and diseases, and is linked to hearing and deafness, inflammatory pain states, cardiovascular disease, osteoporosis. Indeed, many cells use mechanosensitivity to coordinate cell and tissue growth, and failure of these mechanisms may contribute to cancer and other pathologies. Therefore, a molecular understanding of mechanical sensation is important and relevant to a variety of medical indications.