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

Lookup NU author(s): Professor Chris Edwards


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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. © 2005 by The National Academy of Sciences of the USA.

Publication metadata

Author(s): Gorelik J, Zhang Y, Sanchez D, Shevchuk A, Frolenkov G, Lab M, Klenerman D, Edwards C, Korchev Y

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences of the United States of America

Year: 2005

Volume: 102

Issue: 42

Pages: 15000-15005

Print publication date: 18/10/2005

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences


DOI: 10.1073/pnas.0507008102

PubMed id: 16230642


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Funder referenceFunder name
Wellcome Trust
C19021Biotechnology and Biological Sciences Research Council