PDF(Pubmed)
Abstract：
Signal transduction by G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and immunoreceptors converge at the activation of phospholipase C (PLC) for the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). This is a point for second-messenger bifurcation where DAG via protein kinase C (PKC) and IP3 via calcium activate distinct protein targets and regulate cellular functions. IP3 signaling is regulated by multiple calcium influx and efflux proteins involved in calcium homeostasis. A family of lipid kinases belonging to DAG kinases (DGKs) converts DAG to phosphatidic acid (PA), negatively regulating DAG signaling and pathophysiological functions. PA, through a series of biochemical reactions, is recycled to produce new molecules of PIP2. Therefore, DGKs act as a central switch in terminating DAG signaling and resynthesis of membrane phospholipids precursor. Interestingly, calcium and PKC regulate the activation of α and ζ isoforms of DGK that are predominantly expressed in airway and immune cells. Thus, DGK forms a feedback and feedforward control point and plays a crucial role in fine-tuning phospholipid stoichiometry, signaling, and functions. In this review, we discuss the previously underappreciated complex and intriguing DAG/DGK-driven mechanisms in regulating cellular functions associated with asthma, such as contraction and proliferation of airway smooth muscle (ASM) cells and inflammatory activation of immune cells. We highlight the benefits of manipulating DGK activity in mitigating salient features of asthma pathophysiology and shed light on DGK as a molecule of interest for heterogeneous diseases such as asthma.
摘要：
G蛋白偶联受体（GPCRs）的信号转导，受体酪氨酸激酶（RTK）和免疫受体在磷脂酶C（PLC）的激活下会聚，以将磷脂酰肌醇4,5-二磷酸（PIP2）水解为肌醇1,4,5-三磷酸（IP3）和二酰基甘油（DAG）。这是第二信使分叉的点，其中DAG通过蛋白激酶C（PKC）和IP3通过钙激活不同的蛋白质靶标并调节细胞功能。IP3信号传导由参与钙稳态的多种钙流入和流出蛋白调节。属于DAG激酶（DGK）的脂质激酶家族将DAG转化为磷脂酸（PA），负调节DAG信号传导和病理生理功能。PA通过一系列生化反应被回收以产生新的PIP2分子。因此,DGK在终止DAG信号传导和膜磷脂前体的再合成中充当中心开关。有趣的是,钙和PKC调节主要在气道和免疫细胞中表达的DGK的a和z亚型的激活。因此，DGK形成反馈和前馈控制点，在微调磷脂化学计量中起着至关重要的作用，信令,和功能。在这次审查中,我们讨论以前被低估的情结，和有趣的DAG/DGK驱动机制在调节与哮喘相关的细胞功能，如气道平滑肌（ASM）细胞的收缩和增殖，和免疫细胞的炎症激活。我们强调了操纵DGK活性在缓解哮喘病理生理学显着特征方面的益处，并阐明了DGK作为哮喘等异质性疾病的感兴趣分子。
