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J. Biol. Chem., Vol. 282, Issue 11, 8092-8098, March 16, 2007

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AMP-activated Protein Kinase Mediates Carotid Body Excitation by Hypoxia^*

Christopher N. Wyatt¹, Kirsty J. Mustard², Selina A. Pearson^¶3, Mark L Dallas^||4, Lucy Atkinson^||4, Prem Kumar^¶, Chris Peers^||4, D. Grahame Hardie², and A. Mark Evans¹⁵

From the Division of Biomedical Sciences, School of Biology, Bute Building, University of St. Andrews, St. Andrews, Fife. KY16 9TS, Division of Molecular Physiology, College of Life Sciences, Sir James Black Centre, University of Dundee, Dow Street, DD1 5EH, ^¶Department of Physiology, The Medical School, University of Birmingham, Birmingham B15 2TT, and the ^||School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom

Early detection of an O₂ deficit in the bloodstream is essential to initiate corrective changes in the breathing pattern of mammals. Carotid bodies serve an essential role in this respect; their type I cells depolarize when O₂ levels fall, causing voltage-gated Ca²⁺ entry. Subsequent neurosecretion elicits increased afferent chemosensory fiber discharge to induce appropriate changes in respiratory function (1). Although depolarization of type I cells by hypoxia is known to arise from K⁺ channel inhibition, the identity of the signaling pathway has been contested, and the coupling mechanism is unknown (2). We tested the hypothesis that AMP-activated protein kinase (AMPK) is the effector of hypoxic chemotransduction. AMPK is co-localized at the plasma membrane of type I cells with O₂-sensitive K⁺ channels. In isolated type I cells, activation of AMPK using 5-aminoimidazole-4-carboxamide riboside (AICAR) inhibited O₂-sensitive K⁺ currents (carried by large conductance Ca²⁺-activated (BK_Ca) channels and TASK (tandem pore, acid-sensing potassium channel)-like channels, leading to plasma membrane depolarization, Ca²⁺ influx, and increased chemosensory fiber discharge. Conversely, the AMPK antagonist compound C reversed the effects of hypoxia and AICAR on type I cell and carotid body activation. These results suggest that AMPK activation is both sufficient and necessary for the effects of hypoxia. Furthermore, AMPK activation inhibited currents carried by recombinant BK_Ca channels, whereas purified AMPK phosphorylated the subunit of the channel in immunoprecipitates, an effect that was stimulated by AMP and inhibited by compound C. Our findings demonstrate a central role for AMPK in stimulus-response coupling by hypoxia and identify for the first time a link between metabolic stress and ion channel regulation in an O₂-sensing system.

Received for publication, September 11, 2006 , and in revised form, December 14, 2006.

^* 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 Supported by a Wellcome Trust Project Grant.

² Supported by a Wellcome Trust Programme Grant.

³ Supported by a University of Birmingham, Division of Medical Sciences Ph. D. studentship.

⁴ Supported by the British Heart Foundation, the Alzheimer's Research Trust and the Alzheimer's Society.

⁵ To whom correspondence should be addressed. Tel.: 44-1334-463579; Fax: 44-1334-463600; E-mail: ame3{at}st-andrews.ac.uk.

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