1. Cell Biology
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Histidine phosphorylation relieves copper inhibition in the mammalian potassium channel KCa3.1

  1. Shekhar Srivastava
  2. Saswati Panda
  3. Zhai Li
  4. Stephen R Fuhs
  5. Tony Hunter
  6. Dennis J Thiele
  7. Stevan R Hubbard  Is a corresponding author
  8. Edward Y Skolnik  Is a corresponding author
  1. Kimmel Center for Biology and Medicine at the Skirball Institute, United States
  2. Salk Institute for Biological Studies, United States
  3. Duke University School of Medicine, United States
Research Article
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Cite this article as: eLife 2016;5:e16093 doi: 10.7554/eLife.16093

Abstract

KCa2.1, KCa2.2, KCa2.3, and KCa3.1 constitute a family of mammalian small- to intermediate-conductance potassium channels that are activated by calcium-calmodulin. KCa3.1 is unique among these four channels in that activation requires, in addition to calcium, phosphorylation of a single histidine residue (His358) in the cytoplasmic region, by nucleoside diphosphate kinase-B (NPDK-B). The mechanism by which KCa3.1 is activated by histidine phosphorylation is unknown. Histidine phosphorylation is well characterized in prokaryotes but poorly understood in eukaryotes. Here we demonstrate that phosphorylation of His358 activates KCa3.1 by antagonizing copper-mediated inhibition of the channel. Furthermore, we show that activated CD4+ T cells deficient in intracellular copper exhibit increased KCa3.1 histidine phosphorylation and channel activity, leading to increased calcium flux and cytokine production. These findings reveal a novel regulatory mechanism for a mammalian potassium channel and for T-cell activation, and highlight a unique feature of histidine versus serine/threonine and tyrosine as a regulatory phosphorylation site.

Article and author information

Author details

  1. Shekhar Srivastava

    Department of Biochemistry and Molecular Pharmacology, Kimmel Center for Biology and Medicine at the Skirball Institute, New York, United States
    Competing interests
    No competing interests declared.
  2. Saswati Panda

    Department of Biochemistry and Molecular Pharmacology, Kimmel Center for Biology and Medicine at the Skirball Institute, New York, United States
    Competing interests
    No competing interests declared.
  3. Zhai Li

    Department of Biochemistry and Molecular Pharmacology, Kimmel Center for Biology and Medicine at the Skirball Institute, New York, United States
    Competing interests
    No competing interests declared.
  4. Stephen R Fuhs

    Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  5. Tony Hunter

    Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    Tony Hunter, Senior editor, eLife/i.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7691-6993
  6. Dennis J Thiele

    Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States
    Competing interests
    No competing interests declared.
  7. Stevan R Hubbard

    Department of Biochemistry and Molecular Pharmacology, Kimmel Center for Biology and Medicine at the Skirball Institute, New York, United States
    For correspondence
    stevan.hubbard@med.nyu.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2707-9383
  8. Edward Y Skolnik

    Department of Biochemistry and Molecular Pharmacology, Kimmel Center for Biology and Medicine at the Skirball Institute, New York, United States
    For correspondence
    edward.skolnik@med.nyu.edu
    Competing interests
    No competing interests declared.

Funding

National Institute of Allergy and Infectious Diseases (R21AI107443)

  • Stevan R Hubbard

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074192)

  • Dennis J Thiele

National Institute of General Medical Sciences (R01GM084195)

  • Edward Y Skolnik

National Cancer Institute (R01CA194584)

  • Tony Hunter

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Roger J Davis, University of Massachusetts Medical School, United States

Publication history

  1. Received: March 16, 2016
  2. Accepted: August 14, 2016
  3. Accepted Manuscript published: August 19, 2016 (version 1)
  4. Version of Record published: August 30, 2016 (version 2)

Copyright

© 2016, Srivastava et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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