Email Address:
douglas.eaton@emory.edu
Summary of Research Interests:
The goal of my research is to examine the cellular signaling mechanisms
which control all aspects of cellular function including cell growth,
division, and responses to external stimuli. To examine these signaling
mechanisms, I use contemporary methods of cellular and molecular
biology including patch voltage clamp methods and expression of
cloned signaling molecules in Xenopus oocytes and other expression
systems. There are three main areas of cellular signaling research
in my laboratory. First, I have been particularly interested in
the cellular responses which involve steroid hormones and other
lipid molecules particulary as these molecules are responsible for
regulation of total body sodium balance. This work has lead us recently
to examine defects in cellular signaling which may be responsible
for some types of hypertension and electrolyte disorders. Second,
I have been examining the signaling mechanisms responsible for the
responses of renal cells to growth factors and vasoactive substances
like Angiotensin II. This work has direct relevance to understanding
the renal pathology of diabetes. Finally, I am interested in the
signaling mechanisms which control excitability of ion channels
in nerve cells. This work may provide an understanding of the mechanism
of action of general anesthetics.
Selected Publications:
Kemendy, A.E.; Eaton, D.C. Aldosterone alters the open probability
of amiloride-blockable sodium channels in A6 epithelia. Am. J. Physiol.
(Cell) 262:C825-C837; 1992.
Frace, A. M.; Eaton, D.C. Chemical modification of amino groups
on calcium activated K+ channels of GH3 cells. Am. J. Physiol. (Cell)
263:C1081-C1087; 1992.
Ohara, A.; Matsunaga, H.; Eaton, D.C. G-protein activation inhibits
amiloride-blockable, highly selective sodium channels in A6 cells.
Am. J. Physiol. (Cell) 263:C352-C360; 1993.
Matsumoto, P. S.; Ohara, A.; Duchatelle, P.; Eaton, D.C. Tyrosine
kinase regulates epithelial sodium transport in A6 cells. Am. J.
Physiol. (Cell) 264:C246-C250; 1993.
Ling, B. N.; Kokko K. E.; Eaton D. C. PGE2 activates clusters of
apical Cl- channels in principal cells via a cAMP-dependent pathway.
J. Clin. Invest. 93:829-837, 1994.
Matsunaga, H; Ling, BN; and Eaton DC. Ca2+-permeable channel associated
with platelet- derived growth factor receptor in mesangial cells.
Am J Physiol (Cell). 267:C456-465, 1994.
Kokko, K.E.; Matsumoto, P.S.; Ling, B.N.; and Eaton, D.C. Effects
of prostaglandin E2 on amiloride-blockable Na+ channels in a distal
nephron cell line (A6). Am J Physiol (Cell) 267:C1414-1425, 1994.
Seal, E.E.; Eaton, D.C.; Gomez, L.M.; Ma, H.; Ling, B.N. Extracellular
glucose reduces the responsiveness of mesangial cell ion channels
to angiotensin II. Am J Physiol (Fluid and Electrolyte) 269:F389-F397,
1995.
Denson, D.D. ; Worrell, R.T.; and Eaton D.C. A possible role for
phospholipase A2 in the action of general anesthetics. Am J Physiol
(Cell). 270 :C636-C644, 1996.
Ling, B.N.;Zuckerman, J.B.; Lin, C.-M.; Harte, B.J.; McNulty, K.A.;
Smith, P.R.; Gomez, L.; Worrell, R.T.; Eaton, D.C and Kleyman, T.R.
Expression of the cystic fibrosis phenotype in a renal amphibian
epithelial cell line. J. Biol. Chem. 272:594-600, 1997.
Ismailov, I.I.; Kieber-Emmons, T.; Lin, C.-M.; Berdiev, B.K.; Shylonsky,
V.G.; Patton, H.K., Fuller, C.M.; Worrell, R.T.; Zuckerman, J.B.;
Sun, W.; Eaton, D.C; Benos, D.J.; and Kleyman, T.R. Identification
of an amiloride-binding domain within the alpha subunit of the epithelial
sodium channel. J. Biol. Chem. 272:21075-21083, 1997.
Marrero, M.B., Venema, V.J., Ju, H., Li, B., Li, J., Eaton, D.C.,
and Venema, R.C. Regulation of the angiotensin II-induced JAK2 tyrosine
phosphorylation. Roles of SHP-1 and SHP-2. Am J. Physiol. (Cell).
275:C1216-23, 1998.
Jain, L., Chen, X.-J., Brown, L.A., and Eaton, D.C. Nitric oxide
inhibits lung sodium transport through a cGMP-mediated inhibition
of epithelial sodium channels. Am J Physiol (Lung Cell & Molecular
Biology). 274 :L475-L484, 1998.
Marrero, M.B.,Venema, R.C. Venema, V.J., Eaton, D.C. Angiotensin
II-induced tyrosine phosphorylation of STAT1 is regulated by JAK2
and Fyn kinases and MKP-1 phosphatase. J. Biol. Chem. 273:30795-30800,
1998.
Stockand, J.D., N.F. Al-Baldawi, O.K. Al-Khalili, R.T. Worrell,
and D.C. Eaton. S-Adenosyl-L-homocysteine hydrolase regulates aldosterone-induced
Na+ transport. J Biol Chem 274:3842-3850, 1999.
Al-Baldawi, N.F., Stockand, J.D., Al-Khalili, O.K., Yue, G., Eaton,
D.C. Aldosterone Induces Ras Methylation in A6 Epithelia. Am J Physiol
279:C429-C439, 2000.
Becchetti,A., Kemendy,A.E., Stockand,J.D., Sariban-Sohraby,S., and
Eaton,D.C. Methylation Increases the Open Probability of the Epithelial
Sodium Channel in A6 Epithelia. J Biol Chem 275:16550-16559, 2000.
Stockand,J.D., Bao,H.F., Schenck,J., Malik,B., Middleton,P., Schlanger,L.E.,
and Eaton,D.C. Differential effects of protein kinase C on the levels
of epithelial Na+ channel subunit proteins. J Biol Chem 275:25760-25765,
2000.
Jain,L.; Chen, X.-J.; Ramosevac, S.; Brown, L.A.; Eaton, D.C. Expression
of highly selective sodium channels in alveolar type II cells is
determined by culture conditions. Am. J. Physiol. (Lung Cell Mol
Physiol.) 280:L646-58, 2001.
Malik, B.; Schlanger, L.; Al-Khalili, O.; Bao, H.-F.; Yue, G.; Price,
S.R.; Mitch, W.E.; Eaton, D.C. ENaC degradation in A6 Cells by the
ubiquitin-proteasome proteolytic pathway. J. Biol. Chem. 276:12903-10,
2001.
Kleyman, T.R.; Zuckerman, J.B.; Middleton, P.; McNulty, K.; Hu,
B.; Su, X.; An, B.; Eaton, D.C.; Smith, P.R. Cell surface expression
and turnover of the alpha subunit of the epithelial sodium channel.
Am. J. Physiol. (Renal): 281:F213-21, 2001.
Stockand, J.D., Zeltwanger, S.; Bao, H.-F.; Becchetti,A.; Worrell,
R.T.; Eaton,D.C. S-adenosyl-L-homocysteine hydrolase is necessary
for aldosterone-induced activity of epithelial Na+ channels. Am.
J. Physiol. (Cell) 281:C773-85, 2001.
Worrell RT, Bao HF, Denson DD, Eaton DC. Contrasting effects of
cPLA2 on epithelial Na+ transport. Am J Physiol Cell Physiol 281:C147-56,
2001.
Eaton,D.C.; Malik, B.; Saxena, N.C.; Al-Khalili, O.; Yue, G. Mechanisms
of aldosterone's action on epithelial Na+ transport. J. Membrane
Biol. 184:313-319, 2001.
Yue, G.; Merlin, D.; Selsted, M.E.; Lencer, W.I.; Madara, J.L.;
Eaton,D.C. Cryptdin 3 forms anion selective channels in the cytoplasmic
membranes of human embryonic kidney cells. Am. J. Physiol. Gastrointest.
Liver Physiol. 282:G757-65, 2002.
Ma, H.-P.; Li, L.; Zhou, Z.H.; Eaton, D.C.; Warnock, D.G. ATP masks
stretch activation of epithelial sodium channels in A6 distal nephron
cells. Am. J. Physiol. (Renal) 282:F501-F505, 2002.
Yue, G.; Malik, B., Yue, G.; Eaton, D.C. Phosphatidylinositol 4,5-bisphosphate
(PIP2) stimulates epithelial sodium channel activity in A6 cells.
J. Biol. Chem. 277:11965-11969, 2002.
Amiri, F.; Shaw, S.; Wang, X.; Tang, J.; Waller, J.L.; Eaton, D.C.;
Marrero, M.B. Angiotensin II activation of the JAK/STAT pathway
in mesangial cells is altered by high glucose. Kidney Int. 61:1605-16,
2002.
Chen, X.-J.; Eaton, D.C.; Jain, L. Beta-adrenergic regulation of
amiloride-sensitive lung sodium channels. Am. J. Physiol. Lung Cell
Mol. Physiol. 282:L609-620, 2002.
Becchetti, A.; Malik,B.; Yue, G.; Duchatelle, P.; Al-Khalili, O.;
Kleyman, T.R.; Eaton, D.C. Phosphatase inhibitors increase the open
probability of ENaC in A6 cells. Am. J. Physiol. (Renal ) 283:F1030-F1045,
2002.
Fink, A.S.; Wang, Y.; Mendez, T.; Worrell, R.T.; Eaton, D.C.; Nguyen,
T.D.; Lee, S.P. Angiotensin II evokes calcium-mediated signaling
events in isolated dog pancreatic epithelial cells. Pancreas 25:290-5,
2002.
Wang, X.; Shaw, S.; Amiri, F.; Eaton, D.C.; Marrero, M.B. Inhibition
of the Jak/STAT signaling pathway prevents the high glucose-induced
increase in tgf-beta and fibronectin synthesis in mesangial cells.
Diabetes 51:3505-9, 2002.
Matalon, S.; Lazrak, A.; Jain, L.; Eaton, D.C. Invited review: biophysical
properties of sodium channels in lung alveolar epithelial cells.
J. Appl. Physiol. 93:1852-9, 2002.
Rabih I. Bechara, R.I.; Brown, L.A.S.; Eaton, D.C.; Roman, J.; Guidot,
D.M. AT2 receptor expression and apoptosis in alveolar epithelial
cells of ethanol-fed rats. Alcohol Clin Exp Res. 27:1006-14, 2003.
Kelly O, Lin C, Ramkumar M, Saxena NC, Kleyman TR, Eaton DC. Characterization
of an amiloride binding region in the alpha-subunit of ENaC. Am
J Physiol Renal Physiol. 285:F1279-90, 2003.
Hardiman KM, McNicholas-Bevensee CM, Fortenberry J, Myles CT, Malik
B, Eaton DC, Matalon S. Regulation of amiloride-sensitive Na+ transport
by basal nitric oxide. Am J Respir Cell Mol Biol. 30:720-8, 2004.
Chen XJ, Seth S, Yue G, Kamat P, Compans RW, Guidot D, Brown LA,
Eaton DC, Jain L. Influenza virus inhibits ENaC and lung fluid clearance.
Am J Physiol Lung Cell Mol Physiol. 287:L366-73, 2004.
Byas-Smith MG, Li J, Szlam F, Eaton DC, Votaw JR, Denson DD. Isoflurane
induces dopamine transporter trafficking into the cell cytoplasm.
Synapse. 53(2):68-73, 2004.
Ma HP, Al-Khalili O, Ramosevac S, Saxena S, Liang YY, Warnock DG,
Eaton DC. Steroids and exogenous gamma-ENaC subunit modulate cation
channels formed by alpha-ENaC in human B lymphocytes. J Biol Chem.279:33206-12,
2004.
Niisato N, Eaton DC, Marunaka Y. Involvement of cytosolic Cl- in
osmoregulation of alpha-ENaC gene expression. Am J Physiol Renal
Physiol. 287:F932-9, 2004.
Eaton DC, Chen J, Ramosevac S, Matalon S, Jain L. Regulation of
Na+ channels in lung alveolar type II epithelial cells. Proc Am
Thorac Soc. 1:10-16, 2004.
Denson, D.D.; Li, J.; Wang, X.; Eaton, D.C. Activation of BK-channels
in GH3 cells by c-PLA2-dependent G-protein signaling pathway. J
Neurophysiol. 93:3146-56, 2005.
Holtzclaw, J.D.; Morris, L.; Pyatt, R.; Giver, C.; Hoey, J.; Gunn,
R.B.; Eaton, D.C.; Haynes, J.K.; Eisen, A. FIRST: A New Model for
Developing Future Science Faculty. J. College Science Teaching.
in press. 2005.
Malik B, Yue Q, Yue G, Chen XJ, Price SR, Mitch WE, Eaton DC. Role
of Nedd4-2 and poly-ubiquitination in epithelial sodium channel
degradation in untransfected renal A6 cells expressing endogenous
ENaC subunits. Am J Physiol Renal Physiol. 289:F107-16, 2005.
Helms MN, Yu L, Malik B, Kleinhenz DJ, Hart CM, Eaton DC. Role of
SGK1 in nitric oxide inhibition of ENaC in Na+-transporting epithelia.
Am J Physiol Cell Physiol. 289:C717-26, 2005.
Current support:
Title: “Regulation of Na+ Transport in Tight Epithelia”
Principal Investigator: Douglas C. Eaton, Ph.D.
Agency: NIH NIDDK Type: 2R37 DK-37963
Years 16 - 25 Period: 08/01/02 - 07/31/12
This grant examines the mechanisms by which epithelial sodium channels
can be regulated by aldosterone, G-proteins, and inositol lipids;
and examines these regulatory cascades for their ability to alter
sodium channel activity in a physiological context.
Title: “Regulation of Lung Sodium Channels”
Principal Investigator: Lucky Jain, M.D.
Agency: NIH NHLBI Type: 1R01HL63306-01
Years 1 - 4 Period: 05/01/01 - 04/31/05
This is a grant to investigate the mechanisms of regulation of sodium
transport in lung alveolar type II cells with particular emphasis
on the control of lung surface fluid and edema.
Role: Co-PI
Title: “ENaC Assembly, trafficking, and degradation
in lung”
Principal Investigator: Douglas Eaton, Ph.D.
Agency: NIH NHLBI Type: 1R01HL071621
Years 1 - 4 Period: 01/01/03 - 12/31/07
This is a grant to investigate the mechanisms of ENaC Assembly,
trafficking, and degradation in lung alveolar type II cells.
Title: “Project 2: Ethanol effects on lung sodium
and chloride transport and fluid clearance”
Principal Investigator: Douglas Eaton, Ph.D.
Agency: NIH NIAAA Type: 1P50 AA-013757
Years 1 - 5 Period: 01/01/03 - 12/31/08
The aims of this project are to use single channel methods to examine
signaling mechanisms which regulate ENaC expression and the effects
of chronic alcoholism. This is one project of a larger Center Grant,
"Chronic Alcoholism and Lung Pathology" of which Dr. David
Guidot is the Program Director. Role: Project Investigator
Title: “Cellular Signaling and Kidney Function”
Program Director: Douglas Eaton, Ph.D.
Agency: NIH NIDDK Type: 2P01 DK-61521
Years 1 - 5 Period: 09/30/04 - 07/31/09
The aims of this program (consisting of 4 separate projects) are
to examine the cell biology of renal transport proteins that are
responsible for maintaining normal homeostatic balance for sodium,
chloride, hydrogen ion, and urea.
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