INFLUENCE OF PROTEIN/LIPID INTERACTIONS ON SIGNAL TRANSDUCTION

蛋白质/脂质相互作用对信号转导的影响

• 批准号: 5200233
• 负责人: B LITMAN
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5200233
• 关键词: G protein; anesthetics; biological signal transduction; chemical kinetics; cyclic GMP; drug interactions; drug tolerance; enzyme activity; ethanol; lipid bilayer membrane; lipid structure; membrane structure; phospholipids; protein biosynthesis; receptor coupling; rhodopsin; rod cell; unsaturated fatty acids; visual phototransduction

The Influence of Protein-Lipid Interactions on Signal Transduction Litman, B. G protein-coupled receptors are ubiquitous components of signal transduction systems. This project includes an assessment of the role of polyunsaturated phospholipids in modulating G protein-coupled signal transduction and an elucidation of the mechanism of action of ethanol and general anesthetics in these systems. The visual transduction pathway, a prototypical G protein-coupled system, is being used as a model system. The effect of alcohols, anesthetics, and lipid composition on: the kinetics and extent of formation of metarhodopsin II (MII), the G protein activating form of rhodopsin; MII/G protein complex formation; the rate of G protein activation; cGMPphosphodiesterase activation; and the GTPase activity of the G protein are being studied. Short chain alcohols, such as ethanol, are found to be stimulatory, in that they promote MII formation, while longer chain alcohols, such as decanol, are inhibitory. Intermediate length alcohols show a smooth transition from excitatory to inhibitory. The alcohols exert their effect in a lipid dependent fashion, showing a greater range and magnitude of effects in a 16:0,22:6n-3 PC than in 16:0,18:1n-9 PC. The effects in the disk membrane were similar to those observed in 16:0,22:6n-3 PC, consistent with the disk membrane lipid containing about 50 percent of its acyl chains as 22:6n-3. The effects of ethanol, acyl chain composition, and cholesterol are well correlated with changes in phospholipid acyl chain packing free volume, as characterized by the time-resolved fluorescence anisotropy behavior of the membrane probe, diphenylhexatriene. Our observations are best explained by a novel lipid packing model developed in this laboratory, in which the presence of polyunsaturated acyl chains, in mixed saturated-unsaturated acyl chain phospholipids, leads to the formation of lateral domains or clusters in the surface of the membrane. The enhanced meta II formation observed in response to acute ethanol exposure would result in hyperactivity of this pathway, whereas the loss of unsaturated acyl chains in membrane phospholipids observed in chronic exposure to ethanol would be expected to diminish the effect of ethanol on the signalling pathway and may in this way contribute to the tolerance to ethanol developed in chronic ethanol exposure.

蛋白质-脂质相互作用对信号转导的影响 Litman，B. G蛋白偶联受体是信号中普遍存在的成分 转导系统。该项目包括对角色的评估 多不饱和磷脂在调节G蛋白偶联信号中的作用 乙醇的转导及其作用机制的阐明 这些系统中的全身麻醉剂。视觉传导通路， 一个典型的G蛋白偶联系统被用作模型系统。 酒精、麻醉剂和脂质成分对： G蛋白--后视紫红质II(MII)形成的动力学和程度 视紫红质激活形式；MII/G蛋白复合体形成；速率 G蛋白激活、cGMP磷酸二酯酶激活和GTP酶 G蛋白的活性正在研究中。短链醇类 如乙醇，被发现具有刺激性，因为它们促进了MII 形成，而较长的链醇，如癸醇，是抑制。 中长醇表现出从兴奋到平稳的过渡 抑制性的。酒精在脂依赖的情况下发挥作用 时尚，显示出更大范围和规模的效果 16：0、22：6n-3 PC比16：0、18：1n-9 PC低。光盘中的效果 膜与16：0、22：6N-3PC中观察到的膜相似，一致 盘状膜脂含有约50%的酰基 链为22：6N-3。乙醇、酰基链组成和 胆固醇与磷脂酰链的变化密切相关 由时间分辨荧光表征的堆积自由体积 膜探针二苯基己三烯的各向异性行为。我们的 一种新的脂质堆积模型很好地解释了观察结果 在这个实验室中，多不饱和酰基链的存在， 在混合饱和-不饱和酰基链磷脂中，导致 膜表面形成侧域或簇状结构。 急性乙醇反应中观察到的增强的Meta II形成 暴露会导致这一途径的过度活动，而丢失 慢性阻塞性肺疾病患者膜磷脂中不饱和酰基链的变化 接触乙醇预计会减弱乙醇的影响。 在信号通路上，并可能通过这种方式促进耐受性 在慢性酒精暴露中形成的乙醇。