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The large-conductance Ca2+-activated K+ channel is essential for innate immunity

Author

Listed:
  • Jatinder Ahluwalia

    (Department of Medicine University College London)

  • Andrew Tinker

    (Department of Medicine University College London)

  • Lucie H. Clapp

    (Department of Medicine University College London)

  • Michael R. Duchen

    (University College London)

  • Andrey Y. Abramov

    (University College London)

  • Simon Pope

    (Department of Medicine University College London)

  • Muriel Nobles

    (Department of Medicine University College London)

  • Anthony W. Segal

    (Department of Medicine University College London)

Abstract

Neutrophil leukocytes have a pivotal function in innate immunity. Dogma dictates that the lethal blow is delivered to microbes by reactive oxygen species (ROS) and halogens1,2, products of the NADPH oxidase, whose impairment causes immunodeficiency. However, recent evidence indicates that the microbes might be killed by proteases, activated by the oxidase through the generation of a hypertonic, K+-rich and alkaline environment in the phagocytic vacuole3. Here we show that K+ crosses the membrane through large-conductance Ca2+-activated K+ (BKCa) channels. Specific inhibitors of these channels, iberiotoxin and paxilline, blocked oxidase-induced 86Rb+ fluxes and alkalinization of the phagocytic vacuole, whereas NS1619, a BKCa channel opener, enhanced both. Characteristic outwardly rectifying K+ currents, reversibly inhibited by iberiotoxin, were demonstrated in neutrophils and eosinophils and the expression of the α-subunit of the BK channel was confirmed by western blotting. The channels were opened by the combination of membrane depolarization and elevated Ca2+ concentration, both consequences of oxidase activity. Remarkably, microbial killing and digestion were abolished when the BKCa channel was blocked, revealing an essential and unexpected function for this K+ channel in the microbicidal process.

Suggested Citation

  • Jatinder Ahluwalia & Andrew Tinker & Lucie H. Clapp & Michael R. Duchen & Andrey Y. Abramov & Simon Pope & Muriel Nobles & Anthony W. Segal, 2004. "The large-conductance Ca2+-activated K+ channel is essential for innate immunity," Nature, Nature, vol. 427(6977), pages 853-858, February.
    • Handle: RePEc:nat:nature:v:427:y:2004:i:6977:d:10.1038_nature02356
    DOI: 10.1038/nature02356
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    Cited by:

    1. Qijing Chen & Jie Tao & Hongya Hei & Fangping Li & Yunman Wang & Wen Peng & Xuemei Zhang, 2015. "Up-Regulatory Effects of Curcumin on Large Conductance Ca2+-Activated K+ Channels," PLOS ONE, Public Library of Science, vol. 10(12), pages 1-18, December.
    2. Wendy L Imlach & Sarah C Finch & John H Miller & Andrea L Meredith & Julie E Dalziel, 2010. "A Role for BK Channels in Heart Rate Regulation in Rodents," PLOS ONE, Public Library of Science, vol. 5(1), pages 1-7, January.

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