Trafficking and Regulation of the Epithelial Na+ Channel

假如。 。 维持细胞外液容量稳态对于血流动力学稳定和异常 肾脏钠处理与心血管疾病和高血压有关，钠的最终调节 肾脏中的排泄发生在远端肾单位，通过阿米洛瑞敏感上皮传导转运 钠通道（ENaC）。上皮细胞顶膜中的 ENaC 表达和活性是限速步骤 Na 的重吸收不仅在肾脏集合管中，而且在气道上皮和结肠中也有。异常情况 ENaC 功能已在遗传性盐敏感性高血压、肾性盐消耗和囊性高血压中得到证实。 纤维化。本研究的长期目标是了解调节顶端 ENaC 表达的因素 上皮细胞膜以及激素、生理条件和其他通道（例如 作为囊性纤维化跨膜调节因子 CFTR) 控制 ENaC 功能。 ENaC功能的主要控制是； 通过调节Na重吸收细胞膜上的活性通道的数量来发挥作用。频道有 由蛋白水解裂解激活。通道顶端表达的控制是通道递送的函数 膜、通过内吞作用回收以及通道的回收和降解之间的平衡。 对反应性细胞系和天然组织（包括肾和肺）的多次观察表明 通道活动的调节与三个独立亚基的非协调调节有关，这使得 上完全活动的通道。目前的实验将确定网格蛋白的结合伴侣和调控位点 介导的通道内吞作用，内吞途径中各个亚基的命运以及 调节至顶膜的通道再循环。实验旨在确定是否不协调 通道亚基的调节发生在内吞途径中，并且与野生型的差异处理有关 和通过蛋白水解作用激活的裂解通道。该研究旨在确定监管机制 在高血压等疾病状态下可能会受到异常调节。 ??

PROVIDED. . Maintenance of.extracellular fluid volume homeostasis is essential for hemodynamic stability, and abnormalities of renal sodiumhandlinghave been linked to cardiovascular disease and hypertension, Ultimate regulation of sodium excretion in the kidney occurs in the distal nephron via conductive transport through the amiloridesensitive epithelial Na+ channel (ENaC). ENaC expression and activity in the apical membrane of epithelial cells is the rate limiting step in Na+ reabsorption not only in the kidney collecting duce, but in airway epithelia and colon as well. Abnormalitiesof ENaC function have been demonstrated in hereditary forms of salt-sensitive hypertension, renal salt wasting, and cystic Fibrosis. The long term goal of this research is to understand the factors that regulate ENaC expression in the apical membrane of epithelial cells and the mechanisms by which hormones, physiologic conditions and other channels (such as the cystic fibrosis trahsmembrane regulator CFTR) control ENaC function. Major controlof ENaC function is; exerted by regulation of the number of active channels in the membrane of Na+ reabsorbing cells. Channels are activated by proteolytic cleavage. Control of apical expression of the channel is a function of delivery of the channelto the membrane, retrieval through endocytosis, and the balance between recyclingand degradation of the channel. Multiple observations in responsive cell lines and native tissues including kidney and lung have demonstratedthat modulation of channel activity is associated with non-coordinate regulation of the three separate subunits whichmake up the fully active channel. The current experiments will define the binding partners and regulatory sites ofclathrin- mediated endocytosis of the channel,the fate of the individual subunits within the endocytic pathways and the regulation of channel recyclingto the apical membrane. Experiments are designed to determine if non-coordinate regulation of channel subunits takes place in the endocytic pathwayand is related to differential handling of wild type and cleaved channels which have.been activated by proteolysis. The research aims to identify regulatory mechanisms which may be subject to abnormal regulation in disease states such as hypertension. ¿ ¿