Hypertension is a major public health concern because it is an important risk factor for many other diseases including congestive heart failure, stroke, and end-stage renal disease. The constitutive activation of epithelial sodium channels (ENaC) leads to severe hypertension, while subtle stimulation of ENaC may contribute to essential hypertension. Therefore, understanding the regulation of ENaC is important to understand the etiology of hypertension. Our laboratory was among the first to show that ENaC activity requires binding of phosphatidylinositol bis-phosphate (PIP2) to the amino terminal domain of ENaC subunits. We used a tissue culture model of distal nephron sodium transport and we showed that the PIP2 dependent regulation of ENaC is mediated by an adaptor protein, myristoylated alanine-rich C kinase substrate (MARCKS), that binds PIP2 and increases the local concentration of PIP2 near ENaC and, thereby, activates ENaC. The myristoylated amino terminal domain and the basic effector domain of MARCKS both contribute to its function at the apical plasma membrane. The function of MARCKS can be regulated by posttranslational modifications, association with calcium/calmodulin, and proteolysis so that regulation of MARCKS is also important for regulating ENaC.
The aims of this project are to show how MARCKS regulates ENaC in vivo and identify the molecular mechanisms that regulate MARCKS activity at the apical membrane of renal epithelial cells.

Public Health Relevance

The purpose of this project is to identify the mechanism by which amiloride-sensitive epithelial sodium channels are regulated in the kidney by phosphatidylinositol bis- phosphate and myristoylated alanine-rich C-kinase substrate.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01DK099617-01A1
Application #
8700958
Study Section
Digestive Diseases and Nutrition C Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Lucas, Rudolf; Yue, Qiang; Alli, Abdel et al. (2016) The Lectin-like Domain of TNF Increases ENaC Open Probability through a Novel Site at the Interface between the Second Transmembrane and C-terminal Domains of the α-Subunit. J Biol Chem 291:23440-23451
Alli, Abdel A; Bao, Hui-Fang; Liu, Bing-Chen et al. (2015) Calmodulin and CaMKII modulate ENaC activity by regulating the association of MARCKS and the cytoskeleton with the apical membrane. Am J Physiol Renal Physiol 309:F456-63
Reifenberger, Matthew S; Yu, Ling; Bao, Hui-Fang et al. (2014) Cytochalasin E alters the cytoskeleton and decreases ENaC activity in Xenopus 2F3 cells. Am J Physiol Renal Physiol 307:F86-95