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Review
. 2010 Dec 1;588(Pt 23):4659-65.
doi: 10.1113/jphysiol.2010.194225. Epub 2010 Aug 6.

Physiological roles of voltage-gated proton channels in leukocytes

Nicolas Demaurex  1 , Antoun El Chemaly
Affiliations
Review

Physiological roles of voltage-gated proton channels in leukocytes

Nicolas Demaurex et al. J Physiol. .

Abstract

Voltage-gated proton channels are designed to extrude large quantities of cytosolic acid in response to depolarising voltages. The discovery of the Hvcn1 gene and the generation of mice lacking the channel molecule have confirmed several postulated functions of proton channels in leukocytes. In neutrophils and macrophages, proton channels are required for high-level production of superoxide anions by the phagocytic NADPH oxidase, a bactericidal enzyme essential for host defence against infections. In B lymphocytes, proton channels are required for low-level production of superoxide that boosts the production of antibodies. Proton channels sustain the activity of immune cells in several ways. By extruding excess cytosolic acid, proton channels prevent deleterious acidification of the cytosol and at the same time deliver protons required for chemical conversion of the superoxide secreted by membrane oxidases. By moving positive charges across membranes, proton channels limit the depolarisation of the plasma membrane, promoting the electrogenic activity of NADPH oxidases and the entry of calcium ions into cells. Acid extrusion by proton channels is not restricted to leukocytes but also mediates the intracellular alkalinisation required for the activation of spermatozoids. Proton channels are therefore multitalented channels that control male fertility as well as our innate and adaptive immunity.

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Figures

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Nicolas Demaurex (right) and Antoun El Chemaly (left) work in the department of Cell Physiology and Metabolism at the University of Geneva and collaborate to study the role of ion channels in phagocytic white blood cells. Their background is in physiology and cell biophysics, respectively. Using mouse genetics, ion imaging, and electrophysiology, they have determined that VSOP/Hv1 proton channels sustain neutrophils migration and bacterial killing.
Figure 1
Figure 1. Functional roles of voltage-gated proton channels of immune cells
Both neutrophils and B lymphocytes possess a superoxide-generating enzyme, the NADPH oxidase that assembles at the plasma membrane upon phosphorylation. A, neutrophils produce high levels of superoxide radicals (O2−) that help kill bacteria. The large flux of electrons across the oxidase (yellow) depolarises the plasma membrane, whereas the protons released by the oxidation and regeneration of NADPH acidify the cytosol, two conditions that, together with phosphorylation, activate voltage-gated proton channels (blue). Proton channels extrude the cytosolic acid, repolarise the plasma membrane, and deliver extracellular protons used to convert superoxide to hydrogen peroxide (H2O2). Acid extrusion and membrane repolarisation sustain the activity of the oxidase and enhance the entry of calcium across membrane channels to boost cell signalling. B, in activated B lymphocytes, VSOP/Hv1channels also sustain the production of superoxide, but the H2O2 generated diffuses inside cells to oxidise and inactivate the tyrosine phosphatase SHP-1, promoting the phosphorylation of the antigen-bound B cell antigen receptor to boost cell signalling.
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