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. ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-RUS-E (02))
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Ketchum, Christian J
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Butterworth, Michael B; Edinger, Robert S; Silvis, Mark R et al. (2012) Rab11b regulates the trafficking and recycling of the epithelial sodium channel (ENaC). Am J Physiol Renal Physiol 302:F581-90
Butterworth, Michael B (2010) Regulation of the epithelial sodium channel (ENaC) by membrane trafficking. Biochim Biophys Acta 1802:1166-77
Edinger, Robert S; Lebowitz, Jonathan; Li, Hui et al. (2009) Functional regulation of the epithelial Na+ channel by IkappaB kinase-beta occurs via phosphorylation of the ubiquitin ligase Nedd4-2. J Biol Chem 284:150-7
Hallows, Kenneth R; Wang, Huamin; Edinger, Robert S et al. (2009) Regulation of epithelial Na+ transport by soluble adenylyl cyclase in kidney collecting duct cells. J Biol Chem 284:5774-83
Butterworth, Michael B; Edinger, Robert S; Frizzell, Raymond A et al. (2009) Regulation of the epithelial sodium channel by membrane trafficking. Am J Physiol Renal Physiol 296:F10-24
Butterworth, Michael B; Weisz, Ora A; Johnson, John P (2008) Some assembly required: putting the epithelial sodium channel together. J Biol Chem 283:35305-9
Weixel, Kelly M; Edinger, Robert S; Kester, Lauren et al. (2007) Phosphatidylinositol 4-phosphate 5-kinase reduces cell surface expression of the epithelial sodium channel (ENaC) in cultured collecting duct cells. J Biol Chem 282:36534-42
Butterworth, Michael B; Edinger, Robert S; Ovaa, Huib et al. (2007) The deubiquitinating enzyme UCH-L3 regulates the apical membrane recycling of the epithelial sodium channel. J Biol Chem 282:37885-93
Hill, Warren G; Butterworth, Michael B; Wang, Huamin et al. (2007) The epithelial sodium channel (ENaC) traffics to apical membrane in lipid rafts in mouse cortical collecting duct cells. J Biol Chem 282:37402-11
Edinger, Robert S; Yospin, Jeremy; Perry, Clint et al. (2006) Regulation of epithelial Na+ channels (ENaC) by methylation: a novel methyltransferase stimulates ENaC activity. J Biol Chem 281:9110-7

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