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

识别压电机械敏感离子通道激活和敏化的物理刺激

• 批准号: 9120478
• 负责人: Amanda Halley Lewis
• 金额: $ 5.61万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120478
• 关键词: Affect; Afferent Neurons; Arachidonic Acids; Biological; Biological Process; Blood flow; Cations; Cell membrane; Cells; Cholesterol; Data; Dehydration; Development; Drosophila genus; Embryonic Development; Erythrocytes; Glass; Goals; Human; Hyperalgesia; Image; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Ion Channel; Lead; Light; Link; Lipid Bilayers; Mechanics; Mediating; Membrane; Merkel Cells; Mutation; Nociception; Pain; Pain management; Pathway interactions; Physiological Processes; Physiology; Property; Protein Isoforms; Proteins; Recovery; Regulation; Rest; Role; Signal Transduction; Stimulus; Structure; Testing; Time; Tissues; Touch sensation; Vascular Diseases; Vascular System; Vertebrates; allodynia; base; chronic pain; desaturase; design; human disease; inflammatory modulation; insight; novel; pressure; public health relevance; research study; response; restoration; stimulus sensitivity

 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.