Hypoxia Leads to Na,K-ATPase Downregulation via Ca2+ Release-Activated Ca2+ Channels and AMPK Activation

被引：128

作者：

Gusarova, Galina A. ^{[1
]}

Trejo, Humberto E. ^{[1
]}

Dada, Laura A. ^{[1
]}

Briva, Arturo ^{[1
,2
]}

Welch, Lynn C. ^{[1
]}

Hamanaka, Robert B. ^{[1
]}

Mutlu, Goekhan M. ^{[1
]}

Chandel, Navdeep S. ^{[1
]}

Prakriya, Murali ^{[3
]}

Sznajder, Jacob I. ^{[1
]}

机构：

[1] Northwestern Univ, Div Pulm & Crit Care Med, Feinberg Sch Med, Chicago, IL 60611 USA

[2] Univ Republica, Dept Fisiopatol, Fac Med, Montevideo, Uruguay

[3] Northwestern Univ, Dept Mol Pharmacol & Biol Chem, Feinberg Sch Med, Chicago, IL 60611 USA

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2011年 / 31卷 / 17期

关键词：

ALVEOLAR EPITHELIAL-CELLS; KINASE KINASE-BETA; PROTEIN-KINASE; PLASMA-MEMBRANE; PULMONARY-EDEMA; MEDIATED ACTIVATION; FLUID REABSORPTION; MITOCHONDRIAL ROS; UPSTREAM KINASE; CRAC CHANNELS;

D O I：

10.1128/MCB.05114-11

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 alpha 1 (AMPK-alpha 1). We report here that during hypoxia AMPK activation does not require the liver kinase B1 (LKB1) but requires the release of Ca2+ from the endoplasmic reticulum (ER) and redistribution of STIM1 to ER-plasma membrane junctions, leading to calcium entry via Ca2+ release-activated Ca2+ (CRAC) channels. This increase in intracellular Ca2+ induces Ca2+/calmodulin-dependent kinase kinase beta (CaMKK beta)-mediated AMPK activation and Na, K-ATPase down-regulation. Also, in cells unable to generate mitochondrial ROS, hypoxia failed to increase intracellular Ca2+ concentration while a STIM1 mutant rescued the AMPK activation, suggesting that ROS act upstream of Ca2+ 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.

引用

页码：3546 / 3556

页数：11

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