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WIREs Membr Transp Signal

Proton channels in non‐phagocytic cells of the immune system

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Proton channels are expressed in all the cells of the immune system to various degrees. While their function in phagocytic cells, immune cells that engulf bacteria and cell debris for clearance, has been the object of extensive research, the function of proton channels in non‐phagocytic cells has remained more elusive until recently. Further studies have been supported by the discovery of the gene coding for the mammalian proton channel, HVCN1, which has prompted a new wave of research in this area. Recent findings show how proton channels regulate cell function in non‐phagocytic cells of the immune system such as basophils and lymphocytes. WIREs Membr Transp Signal 2013, 2:65–73. doi: 10.1002/wmts.78

Figure 1.

Amino acid sequence of human HVCN1. The threonine residue in the intracellular N‐terminus domain (Thr29, highlighted) is important for channel function, since its phosphorylation enhances channel opening in leukocytes.10 Asp112, on the other hand, is responsible for proton selectivity.5 The two histidines constituting Zn2+ binding sites are indicated,3 together with transmembrane domains (four rectangular boxes).

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Figure 2.

pH regulation by proton channels in basophils. Average [H+]i in basophils stimulated with 1 µg/mL anti‐IgE in the absence ( ) at approximately 30°C and imaged by using confocal microscopy and the shifted excitation and emission ratioing (SEER) of fluorescence approach. The M ± SEM of 25 control cells and 46 cells in Zn2+ is shown, with all data pairs after the star significantly different by Student's t test (P <0.05). Pseudocolor images indicating [H+]i in trios of basophils from this experiment taken after stimulation with anti‐IgE at the indicated time‐points are shown in two rows; the top row is control, the lower in the presence of Zn2+. (Reprinted with permission from Ref 13. Copyright 2002 John Wiley and Sons)

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Figure 3.

Schematic representation of HVCN1 in the context of BCR signaling. Antigen binding to the BCR results in phosphorylation of immunoreceptor tyrosine‐based activation motifs (ITAMs) in the Ig α/β heterodimer by Lyn, a src‐family tyrosine kinase, creating docking sites for Syk.41 This serves to amplify BCR signaling by further recruitment and activation of Syk, which leads to PI3K activation, activation of Akt and increased energy metabolism. Amplification of signaling is negatively regulated by CD22, which is also phosphorylated by Lyn, providing a docking site for protein tyrosine phosphatase SHP‐1.41 SHP‐1 dephosphorylates Syk, counterbalancing ITAM/Syk‐mediated signal amplification. SHP‐1 is inhibited by ROS, which oxidize a cysteine residue in the catalytic site of the enzyme. BCR stimulation results in ROS generated by the NADPH oxidase enzymatic complex, which transfers electrons across the plasma/endosome membrane to molecules of oxygen. The transfer of one electron results in the production of O2·− that combines with protons to form H2O2 and O2, which freely diffuse through the membrane (2O2·−+ 2H+ → H2O2+ O2). ROS generate a localized oxidizing environment that leads to inhibition of SHP‐1, which results in amplification of BCR signals. HVCN1 sustains NADPH oxidase activity through charge compensation and intracellular pH regulation; therefore, in the absence of HVCN1, the oxidizing environment cannot be maintained and this results in SHP‐1 remaining more active, which diminishes BCR signal strength.

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Figure 4.

H+ currents in human peripheral blood lymphocytes. Superimposed H+ currents in a CD19+ B lymphocyte (a) and a CD3+ T lymphocyte (b) elicited by identical families of 4‐second voltage pulses from the holding potential of −60 mV to potentials between −40 and +60 mV, both at pHi 6.0 and pHo 7.5. (c) Current–voltage relationships for H+ currents at the end of the pulses shown in A and B ( , B lymphocyte; , T lymphocyte). (d) Average (±SEM) H+ current densities in lymphocyte subpopulations. H+ current densities were calculated from the H+ current measured at the end of a 4‐second pulse to +60 mV, and normalized to the capacity in each cell. Data are from 63 human B lymphocytes, 46 human T lymphocytes, and 52 Jurkat T cells at pHi 6.0 and pHo 7.5. (Reprinted with permission for Ref 33. Copyright 2002 PNAS)

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