Regulation of mechanosensitive ion channels by membrane lipids

机械敏感离子通道依赖于膜的组成将物理刺激转化为电信号。压电通道介导机械电信号转导，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、振动和本体感觉。PIEZO1和Piezo2是小鼠的必需蛋白质，因为全局敲除是胚胎致死的和细胞特异性的 基因敲除会导致动物出现严重缺陷。在人类中，Piezo通道功能获得和丧失突变 与人类遗传性病理生理学有关。Piezo1基因突变与脱水遗传性口腔细胞增多症有关，这是一种以阳离子通透性增加和红细胞脱水为特征的溶血性贫血。因此，确定调节压电通道门控的蛋白质和脂类是至关重要的。 机械装置。研究表明，磷脂酰肌醇和磷脂酰丝氨酸转位对Piezo有调节作用。 渠道活动。然而，饮食中含有脂肪酸的磷脂如何调节Piezo1和Piezo2的机械门控在很大程度上仍不清楚。我们的长期目标是确定支撑机制 生物活性脂类如何调节机械敏感离子通道。在这项提案中，总体目标是建立饮食脂肪酸调节Piezo通道的分子基础。中心假设是 压电通道的激活和失活由膜的机械性能通过 脂质重塑。提议的研究计划的基本原理是，一旦确定了脂肪酸调节Piezo通道功能的精确机制，就有可能使用脂肪酸来控制 改善血管功能，改善遗传性疾病的效果。这一假说将通过追查来检验 三个具体目标：1)确定脂肪酸组成如何通过改变 膜硬度；2)确定膳食脂肪酸对引起红细胞Piezo1突变的影响 3)验证饱和脂肪酸降低Piezo2活性的假说。我们将利用 功能、生化和生物物理方法，以揭示生物活性脂类对机械感觉的贡献。这项研究计划具有创新性，因为它利用饮食中的脂肪酸来控制Piezo 渠道机械反应。这项拟议的研究具有重要意义，因为它有望在靶向Piezo通道方面产生广泛的翻译影响，涉及血管和神经功能。

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.