Inositol Signalling

肌醇信号传导

• 批准号: 6673239
• 负责人: STEPHEN B SHEARS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 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/6673239
• 关键词: chloride channels; enzyme activity; inhibitor /antagonist; inositol phosphates; intracellular transport; molecular cloning; protein transport; second messengers; site directed mutagenesis; tissue /cell culture; vesicle /vacuole

Summary of Work: An extracellular stimulus evokes a specific response from its target cell - for example, it may command the release or uptake of nutrient, promote neurotransmitter release, or initiate muscle contraction. The information inherent in the stimulus is frequently translated into a format that can then be conveyed by intracellular emissaries: the intracellular levels and hence the activities of these "second messengers" are regulated according to the strength and duration of the original stimulus. This process - signal transduction - is fundamental to how an organism responds and adapts to changes in the environment. Unfortunately, there are many ways it can be disrupted in disease states and by environmental toxins. The adequate treatment of such disturbances requires us to have an understanding of the precise molecular mechanisms that are involved. We study the physiological actions of the inositol polyphosphate second messengers, particularly InsP5 and InsP6. We have discovered that InsP5 is metabolically poised to respond to an appropriate cell stimulus by being metabolized to a novel second messenger - an InsP4 - that regulates Ca2+-dependent Cl- channels in the plasma membrane. These ion channels participate in salt and fluid secretion, smooth muscle contraction, osmoregulation and volume-dependent metabolic effects. We have discovered how an environmental toxin, okadaic acid, perturbs this process and promotes diarrhea. With regards to InsP6, we have shown it is a precursor for other important derivatives: the "pyrophosphorylated" polyphosphates. We are exploring the significance of these novel metabolites, and the information uncovered to date strongly suggests they perform a valuable function: they are "high-energy" molecules whose turnover is regulated by specific extracellular agonists.

工作摘要：细胞外刺激引起了其靶细胞的特定反应 - 例如，它可以释放或吸收营养，促进神经递质释放或启动肌肉收缩。刺激中固有的信息经常被翻译成一种格式，然后可以通过细胞内使者传达：细胞内级别，因此根据原始刺激的强度和持续时间对这些“第二使者”的活性进行调节。这个过程 - 信号转导 - 是生物体如何反应和适应环境变化的基础。不幸的是，在疾病状态和环境毒素中，有很多方法可以破坏。对这种干扰的适当治疗需要我们了解所涉及的精确分子机制。我们研究了肌醇多磷酸第二信使的生理作用，尤其是Insp5和Insp6。我们已经发现，INSP5通过代谢为适当的细胞刺激做出代谢，通过将新型的第二信使（Insp4）代谢，以调节质膜中Ca2+依赖性Cl-通道。这些离子通道参与盐和液体分泌，平滑肌收缩，渗透调节和体积依赖性代谢作用。我们已经发现了环境毒素，冈田酸是如何渗透这一过程并促进腹泻的。关于INSP6，我们表明它是其他重要衍生物的前体：“焦磷酸化”的多磷酸盐。我们正在探索这些新型代谢产物的意义，迄今为止发现的信息强烈表明它们执行了有价值的功能：它们是“高能量”分子，其营业率受特定细胞外激动剂的调节。