An oxygen-sensitive mechanism in regulation of epithelial sodium channel
- aDepartments of Physiology and
- bBioscience, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
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Edited by Lily Y. Jan, University of California, San Francisco, CA, and approved December 24, 2008 (received for review September 26, 2008)
Abstract
Epithelial sodium channels (ENaCs) are of immense importance, controlling Na+ transport across epithelia and thus playing a central role in all aspects of fluid clearance as well as numerous other functions. Regulation of these channels is critical. Here, we show that haem, a regulator of Na+ transport, directly influences ENaC activity, decreasing channel-open probability (but not unitary conductance) in inside-out patches (but not outside-out). Conversely, exposure to the protein in the presence of NADPH and at normoxic O2 tension (requirements for activity of hemeoxygenase) increases channel activity. CO, a product of hemeoxygenase activity, activated ENaC in a manner similar to that of haem plus NADPH. However, under hypoxic conditions, inhibition of ENaC by haem occurred even in the presence of NADPH. These data demonstrate a potent, O2-sensitive mechanism for regulation of ENaC, in which hemeoxygenase acts as the O2 sensor, its substrate and product inhibiting and stimulating (respectively) the activity of ENaC.
Footnotes
- 1To whom correspondence should be addressed. E-mail: y.gu{at}bham.ac.uk
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Author contributions: S.W. and Y.G. designed research; S.W. and Y.G. performed research; S.W. and Y.G. analyzed data; and S.P. and Y.G. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0809100106/DCSupplemental.
- © 2009 by The National Academy of Sciences of the USA
