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J. Biol. Chem., Vol. 280, Issue 50, 41504-41511, December 16, 2005

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Does AMP-activated Protein Kinase Couple Inhibition of Mitochondrial Oxidative Phosphorylation by Hypoxia to Calcium Signaling in O₂-sensing Cells?^*

A. Mark Evans1, Kirsteen J. W. Mustard, Christopher N. Wyatt, Chris Peers¶, Michelle Dipp, Prem Kumar||, Nicholas P. Kinnear, and D. Grahame Hardie

From the Division of Biomedical Sciences, School of Biology, Bute Building, University of St. Andrews, St. Andrews, Fife KY16 9TS, United Kingdom, Division of Molecular Physiology, School of Life Sciences, Wellcome Trust Biocentre, University of Dundee, Dow Street, DD1 5EH, United Kingdom, ^¶Institute for Cardiovascular Research, University of Leeds, Leeds LS2 9JT, United Kingdom, and ^||Department of Physiology, The Medical School, University of Birmingham, Birmingham B15 2TT, United Kingdom

Specialized O₂-sensing cells exhibit a particularly low threshold to regulation by O₂ supply and function to maintain arterial pO₂ within physiological limits. For example, hypoxic pulmonary vasoconstriction optimizes ventilation-perfusion matching in the lung, whereas carotid body excitation elicits corrective cardio-respiratory reflexes. It is generally accepted that relatively mild hypoxia inhibits mitochondrial oxidative phosphorylation in O₂-sensing cells, thereby mediating, in part, cell activation. However, the mechanism by which this process couples to Ca²⁺ signaling mechanisms remains elusive, and investigation of previous hypotheses has generated contrary data and failed to unite the field. We propose that a rise in the cellular AMP/ATP ratio activates AMP-activated protein kinase and thereby evokes Ca²⁺ signals in O₂-sensing cells. Co-immunoprecipitation identified three possible AMP-activated protein kinase subunit isoform combinations in pulmonary arterial myocytes, with 121 predominant. Furthermore, their tissue-specific distribution suggested that the AMP-activated protein kinase-1 catalytic isoform may contribute, via amplification of the metabolic signal, to the pulmonary selectivity required for hypoxic pulmonary vasoconstriction. Immunocytochemistry showed AMP-activated protein kinase-1 to be located throughout the cytoplasm of pulmonary arterial myocytes. In contrast, it was targeted to the plasma membrane in carotid body glomus cells. Consistent with these observations and the effects of hypoxia, stimulation of AMP-activated protein kinase by phenformin or 5-aminoimidazole-4-carboxamide-riboside elicited discrete Ca²⁺ signaling mechanisms in each cell type, namely cyclic ADP-ribose-dependent Ca²⁺ mobilization from the sarcoplasmic reticulum via ryanodine receptors in pulmonary arterial myocytes and transmembrane Ca²⁺ influx into carotid body glomus cells. Thus, metabolic sensing by AMP-activated protein kinase may mediate chemotransduction by hypoxia.

Received for publication, September 13, 2005 , and in revised form, September 29, 2005.

^* This work was supported by The Wellcome Trust Grant 070772 and Biotechnology and Biological Sciences Research Council Grant 01/A/S/07453 (to A. M. E.) and by a contract for an Integrated Project from the European Commission (LSHM-CT-2004-005272) and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit at Dundee (AstraZeneca, Boehringer-Ingleheim, GlaxoSmithKline, Merck & Co., Inc., Merck KgaA, and Pfizer) (to D. G. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Div. of Biomedical Sciences, School of Biology, Bute Bldg., University of St. Andrews, St. Andrews, Fife KY16 9TS, UK. Tel.: 44-1334-463579; Fax: 44-1334-463600; E-mail: ame3{at}st-and.ac.uk.

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