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.

机械敏感性离子通道依赖于膜成分将物理刺激转化为电信号。压电通道介导机械电转导以调节重要的生理过程，包括血管结构和重塑、细胞迁移、红细胞体积、触摸、振动和本体感受。Piezo 1和Piezo 2是小鼠的必需蛋白，因为整体敲除是胚胎致死的和细胞特异性的 敲除导致动物具有严重缺陷。在人类中，压电通道获得和丧失功能突变 与遗传性人类病理生理学有关。Piezo 1突变与脱水遗传性口细胞增多症相关，这是一种以阳离子渗透性增加和红细胞脱水为特征的溶血性贫血。因此，确定调控压电通道门控的蛋白质和脂质是至关重要的 机制等研究表明，磷脂酰肌醇和磷脂酰丝氨酸转位调节Piezo 渠道活动。然而，它仍然在很大程度上是未知的膳食脂肪酸含磷脂调节Piezo 1和Piezo 2机械门控。我们的长期目标是确定 生物活性脂质如何调节机械敏感离子通道。在这个提议中，总体目标是建立饮食脂肪酸调节压电通道的分子基础。核心假设是 压电通道的激活和失活是由膜的机械性质通过以下方式调节的： 脂质重塑拟议研究计划的基本原理是，一旦确定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 血管功能和改善遗传性疾病的影响。这个假设将通过追踪 三个具体目的：1）确定脂肪酸组合物如何通过以下变化调节Piezo 1活性： 膜硬度; 2）确定膳食脂肪酸对引起红细胞的Piezo 1突变的影响 3）测试饱和脂肪酸降低Piezo 2激活的假设。我们将利用 功能，生物化学和生物物理学的方法来揭示生物活性脂质的机械感觉的贡献。这项研究计划是创新的，因为它利用膳食脂肪酸来控制压电 渠道机械响应。这项研究意义重大，因为它有望在靶向参与血管和神经功能的压电通道方面产生广泛的翻译影响。