VSOP/Hv1 proton channels sustain calcium entry, neutrophil migration, and superoxide production by limiting cell depolarization and acidification

J Exp Med. 2010 Jan 18;207(1):129-39. doi: 10.1084/jem.20091837. Epub 2009 Dec 21.


Neutrophils kill microbes with reactive oxygen species generated by the NADPH oxidase, an enzyme which moves electrons across membranes. Voltage-gated proton channels (voltage-sensing domain only protein [VSOP]/Hv1) are required for high-level superoxide production by phagocytes, but the mechanism of this effect is not established. We show that neutrophils from VSOP/Hv1-/- mice lack proton currents but have normal electron currents, indicating that these cells have a fully functional oxidase that cannot conduct protons. VSOP/Hv1-/- neutrophils had a more acidic cytosol, were more depolarized, and produced less superoxide and hydrogen peroxide than neutrophils from wild-type mice. Hydrogen peroxide production was rescued by providing an artificial conductance with gramicidin. Loss of VSOP/Hv1 also aborted calcium responses to chemoattractants, increased neutrophil spreading, and decreased neutrophil migration. The migration defect was restored by the addition of a calcium ionophore. Our findings indicate that proton channels extrude the acid and compensate the charge generated by the oxidase, thereby sustaining calcium entry signals that control the adhesion and motility of neutrophils. Loss of proton channels thus aborts superoxide production and causes a severe signaling defect in neutrophils.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Calcium / metabolism*
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology
  • Cell Movement / drug effects
  • Cell Movement / physiology*
  • Cell Polarity / drug effects
  • Cell Polarity / physiology*
  • Cytosol / metabolism
  • Electron Transport / drug effects
  • Electron Transport / physiology
  • Gramicidin / pharmacology
  • Hydrogen Peroxide / metabolism
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Ion Transport / drug effects
  • Ion Transport / physiology
  • Ionophores / pharmacology
  • Mice
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • Neutrophils / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Superoxides / metabolism


  • Anti-Bacterial Agents
  • Hv1 proton channel, mouse
  • Ion Channels
  • Ionophores
  • Superoxides
  • Gramicidin
  • Hydrogen Peroxide
  • NADPH Oxidases
  • Calcium