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Novartis Found Symp. 2006;272:234-52; discussion 252-8, 274-9.

AMP-activated protein kinase couples mitochondrial inhibition by hypoxia to cell-specific Ca2+ signalling mechanisms in oxygen-sensing cells.

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  • 1Division of Biomedical Sciences, School of Biology, University of St. Andrews, Fife KY16 9TS, UK.


It is generally accepted that relatively mild hypoxia inhibits mitochondrial oxidative phosphorylation in O2-sensing cells, and thereby mediates, in part, cell activation. However, the mechanism by which this process is coupled to discrete, cell-specific Ca2+ signalling mechanisms remains elusive. We considered the possibility that hypoxia may increase the cellular ATP/AMP ratio, increase the activity of AMP-activated protein kinase (AMPK) and thereby evoke Ca2+ signals in O2-sensing cells. Co-immunoprecipitation identified alpha1beta2gamma1 as the primary AMPK isozyme in pulmonary arterial smooth muscle, whilst the tissue-specific distribution of AMPK activities and their activation by hypoxia suggested that the AMPK-alpha1 catalytic subunit isoform is key to the regulation of O2-sensing cells. Strikingly, 3D reconstruction of immunofluorescence images showed AMPK-alpha1 to be located throughout the cytoplasm of pulmonary arterial smooth muscle cells and, by contrast, targeted to the plasma membrane in carotid body glomus cells. Consistent with these observations Ca2+ imaging, tension recording and electrophysiology demonstrated that AMPK, like hypoxia, activates each cell type via discrete Ca2+ signalling mechanisms: cyclic ADP-ribose-dependent Ca2+ mobilization from the sarcoplasmic reticulum via ryanodine receptors in pulmonary arterial smooth muscle cells and voltage-gated Ca2+ influx into carotid body glomus cells. Thus, metabolic-sensing by AMPK underpins the cell-specific response of O2-sensing cells to hypoxia.

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