AMPK controls epithelial Na+ channels through Nedd4-2 and causes an epithelial phenotype when mutated

Joana Almaca, Patthara Kongsuphol, Bernhard Hieke, Jiraporn Ousingsawat, Benoit Viollet, Rainer Schreiber, Margarida D. Amaral, Karl Kunzelmann

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

The metabolic sensor adenosine-monophosphate-activated kinase (AMPK) detects the cellular energy status and adjusts metabolic activity according to the cytosolic AMP to ATP ratio. Na+ absorption by epithelial Na + channels (ENaC) is a highly energy-consuming process that is inhibited by AMPK. We show that the catalytic subunit α1 of AMPK inhibits ENaC in epithelial tissues from airways, kidney, and colon and that AMPK regulation of ENaC is absent in AMPKα1-/- mice. These mice demonstrate enhanced electrogenic Na+ absorption that leads to subtle changes in intestinal and renal function and may also affect Na+ absorption and mucociliary clearance in the airways. We demonstrate that AMPK uses the ubiquitin ligase Nedd4-2 to inhibit ENaC by increasing ubiquitination and endocytosis of ENaC. Thus, enhanced expression of epithelial Na+ channels was detected in colon, airways, and kidney of AMPKα1-/- mice. Therefore, AMPKα1 is a physiologically important regulator of electrogenic Na+ absorption and may provide a novel pharmacological target for controlling epithelial Na+ transport.

Original languageEnglish (US)
Pages (from-to)713-721
Number of pages9
JournalPflugers Archiv European Journal of Physiology
Volume458
Issue number4
DOIs
StatePublished - Aug 1 2009
Externally publishedYes

Fingerprint

Epithelial Sodium Channels
Adenosine Monophosphate
Phosphotransferases
Phenotype
Kidney
Colon
Bridge clearances
Mucociliary Clearance
Ubiquitination
Ligases
Ubiquitin
Endocytosis
Catalytic Domain
Epithelium
Adenosine Triphosphate
Pharmacology
Tissue
Sensors

Keywords

  • AMPK
  • AMPKα1
  • ENaC
  • Epithelial Na+ channel
  • Knockout

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

Cite this

AMPK controls epithelial Na+ channels through Nedd4-2 and causes an epithelial phenotype when mutated. / Almaca, Joana; Kongsuphol, Patthara; Hieke, Bernhard; Ousingsawat, Jiraporn; Viollet, Benoit; Schreiber, Rainer; Amaral, Margarida D.; Kunzelmann, Karl.

In: Pflugers Archiv European Journal of Physiology, Vol. 458, No. 4, 01.08.2009, p. 713-721.

Research output: Contribution to journalArticle

Almaca, J, Kongsuphol, P, Hieke, B, Ousingsawat, J, Viollet, B, Schreiber, R, Amaral, MD & Kunzelmann, K 2009, 'AMPK controls epithelial Na+ channels through Nedd4-2 and causes an epithelial phenotype when mutated', Pflugers Archiv European Journal of Physiology, vol. 458, no. 4, pp. 713-721. https://doi.org/10.1007/s00424-009-0660-4
Almaca, Joana ; Kongsuphol, Patthara ; Hieke, Bernhard ; Ousingsawat, Jiraporn ; Viollet, Benoit ; Schreiber, Rainer ; Amaral, Margarida D. ; Kunzelmann, Karl. / AMPK controls epithelial Na+ channels through Nedd4-2 and causes an epithelial phenotype when mutated. In: Pflugers Archiv European Journal of Physiology. 2009 ; Vol. 458, No. 4. pp. 713-721.
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