Hypoxia leads to Na,K-ATPase downregulation via Ca 2+ release-activated Ca 2+ channels and AMPK activation

Galina A. Gusarova, Humberto E. Trejo, Laura A. Dada, Arturo Briva, Lynn C. Welch, Robert B. Hamanaka, Gökhan M. Mutlu, Navdeep S. Chandel, Murali Prakriya, Jacob I. Sznajder*

*Corresponding author for this work

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

To maintain cellular ATP levels, hypoxia leads to Na,K-ATPase inhibition in a process dependent on reactive oxygen species (ROS) and the activation of AMP-activated kinase α1 (AMPK-α1). We report here that during hypoxia AMPK activation does not require the liver kinase B1 (LKB1) but requires the release of Ca 2+ from the endoplasmic reticulum (ER) and redistribution of STIM1 to ER-plasma membrane junctions, leading to calcium entry via Ca 2+ release-activated Ca 2+ (CRAC) channels. This increase in intracellular Ca 2+ induces Ca 2+/calmodulin-dependent kinase kinase β (CaMKKβ)-mediated AMPK activation and Na,K-ATPase downregulation. Also, in cells unable to generate mitochondrial ROS, hypoxia failed to increase intracellular Ca 2+ concentration while a STIM1 mutant rescued the AMPK activation, suggesting that ROS act upstream of Ca 2+ signaling. Furthermore, inhibition of CRAC channel function in rat lungs prevented the impairment of alveolar fluid reabsorption caused by hypoxia. These data suggest that during hypoxia, calcium entry via CRAC channels leads to AMPK activation, Na,K-ATPase downregulation, and alveolar epithelial dysfunction.

Original languageEnglish (US)
Pages (from-to)3546-3556
Number of pages11
JournalMolecular and cellular biology
Volume31
Issue number17
DOIs
StatePublished - Sep 1 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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