Regulation of mechanosensitive ion channels by membrane lipids

膜脂对机械敏感离子通道的调节

• 批准号: 10984747
• 负责人: Valeria Vasquez
• 金额: $ 33.54万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10984747
• 关键词: Regulation; mechanosensitive; ion; channels; membrane

Mechanosensitive ion channels rely on membrane composition to transduce physical stimuli into electrical signals. Piezo channels mediate mechanoelectrical transduction to regulate crucial physiological processes, including vascular architecture and remodeling, cell migration, erythrocyte volume, touch, vibration, and proprioception. Piezo1 and Piezo2 are essential proteins in mice, as global knockouts are embryonic lethal and cell-specific knockouts result in animals with severe defects. In humans, Piezo channels gain- and loss-of-function mutations have been associated with hereditary human pathophysiologies. Mutations in Piezo1 are associated with dehydrated hereditary stomatocytosis, a hemolytic anemia characterized by increased cation permeability and dehydrated erythrocytes. Hence, it is essential to determine the proteins and lipids that regulate Piezo channels gating mechanisms. It has been shown that phosphoinositides and phosphatidylserine translocation regulate Piezo channels activity. However, it remains largely unknown how dietary fatty acids-containing phospholipids modulate Piezo1 and Piezo2 mechanical gating. Our long-term goal is to determine the mechanisms underpinning how bioactive lipids modulate mechanosensitive ion channels. In this proposal, the overall objective is to establish the molecular basis underlying Piezo channels modulation by dietary fatty acids. The central hypothesis is that Piezo channels activation and inactivation are regulated by the mechanical properties of the membrane via lipid remodeling. The rationale for the proposed research plan is that once the precise mechanisms are determined whereby fatty acids modulate Piezo channels function, it will be possible to use fatty acids to control vascular function and ameliorate the effects of hereditary disorders. The hypothesis will be tested by pursuing three Specific Aims: 1) Determine how fatty acid composition modulates Piezo1 activity through changes in membrane stiffness; 2) Determine the effect of dietary fatty acids on Piezo1 mutations causing red blood cell disorders; and 3) Test the hypothesis that saturated fatty acids decrease Piezo2 activation. We will leverage functional, biochemical, and biophysical approaches to uncover the contribution of bioactive lipids to mechanosensation. The research plan is innovative because it exploits the use of dietary fatty acids to control Piezo channels mechanical response. The proposed research is significant because it is expected to have broad translational impact in targeting Piezo channels, involved in vascular and neuronal function.

机械敏感离子通道依靠膜成分将物理刺激转换为电信号。压电通道介导机电转导来调节关键的生理过程，包括血管结构和重塑、细胞迁移、红细胞体积、触觉、振动和本体感觉。 Piezo1 和 Piezo2 是小鼠体内必需的蛋白质，因为全局敲除具有胚胎致死性和细胞特异性 基因敲除会导致动物出现严重缺陷。在人类中，压电引导功能获得和丧失的突变 与遗传性人类病理生理学有关。 Piezo1 突变与脱水遗传性口细胞增多症有关，这是一种溶血性贫血，其特征是阳离子通透性增加和红细胞脱水。因此，确定调节压电通道门控的蛋白质和脂质至关重要 机制。研究表明，磷酸肌醇和磷脂酰丝氨酸易位可调节压电 渠道活动。然而，含膳食脂肪酸的磷脂如何调节 Piezo1 和 Piezo2 机械门控仍然很大程度上未知。我们的长期目标是确定支撑机制 生物活性脂质如何调节机械敏感离子通道。在该提案中，总体目标是建立膳食脂肪酸调节压电通道的分子基础。中心假设是 压电通道的激活和失活是通过膜的机械特性来调节的 脂质重塑。拟议研究计划的基本原理是，一旦确定了脂肪酸调节压电通道功能的精确机制，就有可能使用脂肪酸来控制 血管功能并改善遗传性疾病的影响。该假设将通过追求来检验 三个具体目标：1) 确定脂肪酸成分如何通过变化来调节 Piezo1 活性 膜刚度； 2) 确定膳食脂肪酸对引起红细胞的 Piezo1 突变的影响 疾病； 3) 检验饱和脂肪酸降低 Piezo2 激活的假设。我们将利用 功能、生物化学和生物物理方法揭示生物活性脂质对机械感觉的贡献。该研究计划具有创新性，因为它利用膳食脂肪酸来控制压电 通道机械反应。拟议的研究意义重大，因为预计它将对涉及血管和神经元功能的压电通道产生广泛的转化影响。