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Ion Channel Regulation by the LKB1-AMPK Signalling Pathway: The Key to Carotid Body Activation by Hypoxia and Metabolic Homeostasis at the Whole Body Level

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Arterial Chemoreception

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 758))

Abstract

Our recent investigations provide further support for the proposal that, consequent to inhibition of mitochondrial oxidative phosphorylation, activation of AMP-activated protein kinase (AMPK) mediates carotid body excitation by hypoxia. Consistent with the effects of hypoxia, intracellular dialysis from a patch pipette of an active (thiophosphorylated) recombinant AMPK heterotrimer (α2β2γ1) or application of the AMPK activators AICAR and A769662: (1) Inhibited BKCa currents and TASK K+ currents in rat carotid body type I cells; (2) Inhibited whole-cell currents carried by KCa1.1 and TASK3, but not TASK1 channels expressed in HEK293 cells; (3) Triggered carotid body activation. Furthermore, preliminary studies using mice with conditional knockout in type I cells of the primary upstream kinase that activates AMPK in response to metabolic stresses, LKB1, appear to confirm our working hypothesis. Studies on mice with knockout of the catalytic α1 subunit and α2 subunits of AMPK, respectively, have proved equally consistent. Accumulating evidence therefore suggests that the LKB1-AMPK signalling pathway is necessary for hypoxia-response coupling by the carotid body, and serves to regulate oxygen and therefore energy supply at the whole body level.

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Acknowledgements

These studies were supported by a Programme Grant from the Wellcome Trust (81195, to AME, CP and DGH).

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Authors and Affiliations

  1. Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK

    A. Mark Evans

  2. Division of Cardiovascular and Neuronal Remodelling, LIGHT, Faculty of Medicine and Health, Garstang Building (level 5), University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK

    Chris Peers

  3. Department of Neuroscience, Cell Biology and Physiology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH, 45435, USA

    Christopher N. Wyatt

  4. School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    Prem Kumar

  5. College of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK

    D. Grahame Hardie

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  1. A. Mark Evans
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  2. Chris Peers
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  3. Christopher N. Wyatt
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  4. Prem Kumar
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  5. D. Grahame Hardie
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Corresponding author

Correspondence to A. Mark Evans .

Editor information

Editors and Affiliations

  1. Dept. Biology, McMaster University, Main St. W. 1280, Hamilton, L8S 4K1, Ontario, Canada

    Colin A. Nurse

  2. Facultad de Medicina, Depto. Bioquímica y Biología, Universidad de Valladolid, C\ Ramón y Cajal 7, Valladolid, 47005, Spain

    Constancio Gonzalez

  3. Fac. Medicine & Health, Division of Cardiovascular &, University of Leeds, Clarendon Way, Leeds, LS2 9JT, United Kingdom

    Chris Peers

  4. , Biological Sciences Div &, University of Chicago, South Maryland Avenue 5841, Chicago, 60637, Illinois, USA

    Nanduri Prabhakar

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Evans, A.M., Peers, C., Wyatt, C.N., Kumar, P., Hardie, D.G. (2012). Ion Channel Regulation by the LKB1-AMPK Signalling Pathway: The Key to Carotid Body Activation by Hypoxia and Metabolic Homeostasis at the Whole Body Level. In: Nurse, C., Gonzalez, C., Peers, C., Prabhakar, N. (eds) Arterial Chemoreception. Advances in Experimental Medicine and Biology, vol 758. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4584-1_11

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