Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 102 (42): 15000-15005

Copyright © 2005 by the National Academy of Sciences.


Aldosterone acts via an ATP autocrine/paracrine system: The Edelman ATP hypothesis revisited

Julia Gorelik * {dagger}, Yanjun Zhang {dagger}, {ddagger}, Daniel Sánchez {ddagger}, Andrew Shevchuk {ddagger}, Gregory Frolenkov §, Max Lab {ddagger}, David Klenerman ¶, Christopher Edwards ||, **, and Yuri Korchev {ddagger}, **

{ddagger}Division of Medicine, Imperial College London, Medical Research Council Clinical Sciences Centre, London W12 0NN, United Kingdom; *National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom; §Department of Physiology, University of Kentucky, Chandler Medical Center, Lexington, KY 40536; Department of Chemistry, Cambridge University, Cambridge CB2 1EW, United Kingdom; and ||Office of the Vice Chancellor, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 7RU, United Kingdom

Communicated by Maria Iandolo New, Weill Medical College of Cornell University, New York, NY, August 22, 2005

Received for publication July 19, 2005.

Abstract: Aldosterone, the most important sodium-retaining hormone, was first characterized >50 years ago. However, despite numerous studies including the classical work of Isidore S. "Izzy" Edelman showing that aldosterone action depended on ATP production, the mechanism by which it activates sodium reabsorption via the epithelial sodium channel remains unclear. Here, we report experiments that suggest that one of the key steps in aldosterone action is via an autocrine/paracrine system. The hormone stimulates ATP release from the basolateral side of the target kidney cell. Prevention of ATP accumulation or its removal blocks aldosterone action. ATP then acts via a purinergic mechanism to produce contraction of small groups of adjacent epithelial cells. Patch clamping demonstrates that it is these contracted cells that have channel activity. With progressive recruitment of contracting cells, there is then a parallel increase in transepithelial electrical conductance. In common with other stimuli of sodium transport, this pathway involves phosphatidylinositol 3-kinase. Inhibition of phosphatidylinositol 3-kinase blocks both cell contraction and conductance. We put forward the hypothesis that redistribution of the cell volume caused by the lateral contraction results in apical swelling and that this change, in turn, disrupts the epithelial sodium channel interaction with the F-actin cytoskeleton, opening the channel and hence increasing sodium transport.

Key Words: scanning ion conductance microscopy • scanning probe microscopy • epithelial sodium channel • renal epithelium

Author contributions: J.G., Y.Z., C.E., and Y.K. designed research; J.G., Y.Z., D.S., A.S., and G.F. performed research; J.G., Y.Z., D.S., A.S., G.F., M.L., and Y.K. analyzed data; Y.Z., D.K., and Y.K. contributed new reagents/analytic tools; A.S., M.L., and D.K. discussed results; and J.G., Y.Z., D.S., C.E., and Y.K. wrote the paper;.

Abbreviations: SICM, scanning ion conductance microscopy; PI3K, phosphatidylinositol 3-kinase; Gt, transepithelial electrical conductance.

{dagger} J.G. and Y.Z. contributed equally to this work.

** To whom correspondence may be addressed. E-mail: y.korchev{at} or c.edwards{at}

© 2005 by The National Academy of Sciences of the USA

Basal Release of ATP: An Autocrine-Paracrine Mechanism for Cell Regulation.
R. Corriden and P. A. Insel (2010)
Science Signaling 3, re1
   Abstract »    Full Text »    PDF »
Potassium softens vascular endothelium and increases nitric oxide release.
H. Oberleithner, C. Callies, K. Kusche-Vihrog, H. Schillers, V. Shahin, C. Riethmuller, G. A. MacGregor, and H. E. de Wardener (2009)
PNAS 106, 2829-2834
   Abstract »    Full Text »    PDF »
Effects of [Ca2+]i and pH on epithelial Na+ channel activity of cultured mouse cortical collecting ducts.
Y. Gu (2008)
J. Exp. Biol. 211, 3167-3173
   Abstract »    Full Text »    PDF »
Effect of Basolateral Adenosine Triphosphate on Chloride Secretion by Bovine Oviductal Epithelium.
N. Keating and L.R. Quinlan (2008)
Biol Reprod 78, 1119-1126
   Abstract »    Full Text »    PDF »
Sodium-Dependent Regulation of Renal Amiloride-Sensitive Currents by Apical P2 Receptors.
S. S.P. Wildman, J. Marks, C. M. Turner, L. Yew-Booth, C. M. Peppiatt-Wildman, B. F. King, D. G. Shirley, W. Wang, and R. J. Unwin (2008)
J. Am. Soc. Nephrol. 19, 731-742
   Abstract »    Full Text »    PDF »
Plasma sodium stiffens vascular endothelium and reduces nitric oxide release.
H. Oberleithner, C. Riethmuller, H. Schillers, G. A. MacGregor, H. E. de Wardener, and M. Hausberg (2007)
PNAS 104, 16281-16286
   Abstract »    Full Text »    PDF »
Basolateral P2X4-like receptors regulate the extracellular ATP-stimulated epithelial Na+ channel activity in renal epithelia.
Y. Zhang, D. Sanchez, J. Gorelik, D. Klenerman, M. Lab, C. Edwards, and Y. Korchev (2007)
Am J Physiol Renal Physiol 292, F1734-F1740
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882