REGULATION OF SODIUM TRANSPORT IN TIGHT EPITHELIA

Summary

Principal Investigator: Douglas Eaton
Abstract: The goals of this proposal are to examine cellular mechanisms which regulate Na transport across renal tissue. Understanding Na transport is essential for understanding how the body maintains stable, long term blood pressure. Despite previous descriptions of individual molecular elements which regulate Na channels, the complete signaling cascades which contain these elements have not been described. Therefore, this application proposes to investigates, using patch clamp techniques supplemented by direct biochemical measurements, the signaling cascades which regulate sodium channels in a cellular model of the mammalian kidney principal cell, the Xenopus distal nephron cell line (A6). The specific aims for the proposed grant period will investigate three signaling cascades. The aims are: (1) examine the regulation of sodium channels by heterotrimeric G protein signaling cascades. Activation of an apical G protein inhibits Na channels through a mechanism which also involves protein kinase C, but little else is known about the pathway including which class of G protein is responsible for Na channel regulation; whether luminal receptors activate the G proteins; what molecules are activated by the G proteins; and what the final effects on Na channels are? (2) Investigate the mechanisms by which steroid hormones increase sodium channel activity. Methylation of excised, apical membranes induces sodium channel activity similar to the action of aldosterone and that the methylation reaction is augmented by G protein stimulation. Questions to be addressed for this aim are what is the target for methylation? Is it a small G protein like Ras? Is O- carboxy-methyl transferase activity altered by aldosterone? Is the activity of methyl transferase controlled by endogenous inhibitors like S-adenosyl homocysteine? (3) Investigate the mechanisms by which insulin-like growth factor 1 (IGF-1) Increase sodium channel activity. Determine the role of tyrosine kinases in the regulation of sodium channels. Both insulin and IGF-1 increase sodiu, transport and generalized inhibition of tyrosine kinases blocks the effect of IGF-1 and insulin. In addition, at least one subunit of the sodium channel is a target for IGF-1 mediated tyrosine phosphorylation. To further examine the role of insulin, IGF-1, and tyrosine kinases in regulating sodium channels, several questions will be answered is there any difference in the action of insulin and IGF-1 on A6 cells? Which Na channel subunits are tyrosine phosphorylated by IGF-1? Are there effects of tyrosine kinases in the absence of insulin or IGF-1?
Funding Period: 1987-08-01 - 2002-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Role of Nedd4-2 and polyubiquitination in epithelial sodium channel degradation in untransfected renal A6 cells expressing endogenous ENaC subunits
    B Malik
    Dept of Physiology, Emory University School of Medicine, Atlanta, GA 30322, USA
    Am J Physiol Renal Physiol 289:F107-16. 2005
  2. ncbi Aldosterone-induced increases in superoxide production counters nitric oxide inhibition of epithelial Na channel activity in A6 distal nephron cells
    Ling Yu
    The Center for Cell and Molecular Signaling, Department of Physiology, Emory University School of Medicine, Whitehead Biomedical Research Bldg, 615 Michael St, Atlanta, GA 30322, USA
    Am J Physiol Renal Physiol 293:F1666-77. 2007
  3. pmc Single-channel analysis of functional epithelial sodium channel (ENaC) stability at the apical membrane of A6 distal kidney cells
    Ling Yu
    Center for Cell and Molecular Signaling, Department of Physiology, Emory University School of Medicine, Whitehead Biomedical Research Bldg 615 Michael St, Atlanta, GA 30322, USA
    Am J Physiol Renal Physiol 295:F1519-27. 2008
  4. pmc Biphasic regulation of ENaC by TGF-{alpha} and EGF in renal epithelial cells
    Lian Liu
    Emory Univ School of Medicine, Department of Physiology, Whitehead Bldg, Rm 655, Atlanta, GA 30322, USA
    Am J Physiol Renal Physiol 296:F1417-27. 2009

Scientific Experts

Detail Information

Publications4

  1. ncbi Role of Nedd4-2 and polyubiquitination in epithelial sodium channel degradation in untransfected renal A6 cells expressing endogenous ENaC subunits
    B Malik
    Dept of Physiology, Emory University School of Medicine, Atlanta, GA 30322, USA
    Am J Physiol Renal Physiol 289:F107-16. 2005
    ..The results reported here suggest that the ubiquitin-proteasome proteolytic pathway is an important determinant of ENaC function in untransfected renal cells expressing endogenous ENaC...
  2. ncbi Aldosterone-induced increases in superoxide production counters nitric oxide inhibition of epithelial Na channel activity in A6 distal nephron cells
    Ling Yu
    The Center for Cell and Molecular Signaling, Department of Physiology, Emory University School of Medicine, Whitehead Biomedical Research Bldg, 615 Michael St, Atlanta, GA 30322, USA
    Am J Physiol Renal Physiol 293:F1666-77. 2007
    ....
  3. pmc Single-channel analysis of functional epithelial sodium channel (ENaC) stability at the apical membrane of A6 distal kidney cells
    Ling Yu
    Center for Cell and Molecular Signaling, Department of Physiology, Emory University School of Medicine, Whitehead Biomedical Research Bldg 615 Michael St, Atlanta, GA 30322, USA
    Am J Physiol Renal Physiol 295:F1519-27. 2008
    ....
  4. pmc Biphasic regulation of ENaC by TGF-{alpha} and EGF in renal epithelial cells
    Lian Liu
    Emory Univ School of Medicine, Department of Physiology, Whitehead Bldg, Rm 655, Atlanta, GA 30322, USA
    Am J Physiol Renal Physiol 296:F1417-27. 2009
    ....