The voltage dependence of NADPH oxidase reveals why phagocytes need proton channels

DeCoursey, Thomas E.; Morgan, Deri; Cherny, Vladimir V.

doi:10.1038/nature01523

Cited by 294 publications

(369 citation statements)

References 28 publications

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“…Voltage-gated proton-selective conductances have been described in molluscan neurons (38) as well as in various non-excitable mammalian cell types in which they help maintain the function of NADPH oxidase (39). Although these currents exhibit classic voltage-, time-, and pH-dependent gating properties, indirect evidence points to a permeation mechanism other than that expected for a classic, water-filled ion channel pore (40).…”

Section: Capsaicin-induced Changes Of the Ph I In Rat Dorsal Rootmentioning

confidence: 99%

TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons

Hellwig

Plant

Janson

et al. 2004

Journal of Biological Chemistry

139

101

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The low extracellular pH of inflamed or ischemic tissues enhances painful sensations by sensitizing and activating the vanilloid receptor 1 (TRPV1). We report here that activation of TRPV1 results in a marked intracellular acidification in nociceptive dorsal root ganglion neurons and in a heterologous expression system. A characterization of the underlying mechanisms revealed a Ca 2؉ -dependent intracellular acidification operating at neutral pH and an additional as yet unrecognized direct proton conductance through the poorly selective TRPV1 pore operating in acidic extracellular media. Large organic cations permeate through the activated TRPV1 pore even in the presence of physiological concentrations of Na ؉ , Mg 2؉ , and Ca 2؉ . The wide pore and the unexpectedly high proton permeability of TRPV1 point to a proton hopping permeation mechanism along the water-filled channel pore. In acidic media, the high relative proton permeability through TRPV1 defines a novel proton entry mechanism in nociceptive neurons.During ischemia or inflammation, pain sensation is augmented by the acidic extracellular pH (pH ext ). 1 A␦-and C-fiber neurons sense extracellular acid by means of two different classes of cation channels, namely TRPV1, the founding member of the vanilloid receptor-like transient receptor potential channel family (1, 2), and the acid-sensing ion channels (ASIC) (3, 4). Both channel types are expressed in small diameter dorsal root ganglion (DRG) neurons, and their role in mediating inflammatory hyperalgesia has been proven by gene deletion techniques (5-7). TRPV1, a poorly selective cation channel, integrates multiple pain-inducing stimuli, including noxious heat, vanilloids, and acidic extracellular pH (1, 8 -10). Inflammatory mediators such as bradykinin, serotonin, histamine, or prostaglandins further stimulate TRPV1 activity either by protein kinase C-dependent signals (11-13), by a release from a phosphatidylinositol 4,5-bisphosphate-dependent inhibition (14,15), by formation of 12-lipoxygenase products (16), or by a protein kinase A-mediated recovery from inactivation (17). Furthermore, extracellular acidification shifts the activation of TRPV1 toward lower temperature or ligand thresholds by protonation of an amino acid located in the vicinity of the pore loop (18). Although the role of the external pH ext in modulating TRPV1 activity is well established, a possible impact of TRPV1 activation on the intracellular pH has not been studied.A Ca 2ϩ influx component through activated voltage-or ligand-gated cation channels has been recognized to lower the intracellular pH (pH i ) in neurons or in neuroendocrine cells (19,20). We therefore asked the question whether activation of the Ca 2ϩ -permeable TRPV1 may also mediate intracellular acidification in native rat dorsal root ganglion neurons or in a heterologous expression system. Our results provide evidence for two independent TRPV1-mediated acidification signals, including an as yet unrecognized direct proton conductance through the activated TRPV1 p...

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Section: Capsaicin-induced Changes Of the Ph I In Rat Dorsal Rootmentioning

confidence: 99%

TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons

Hellwig

Plant

Janson

et al. 2004

Journal of Biological Chemistry

139

101

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“…The oxidase is electrogenic and voltage dependent (Henderson et al, 1987;DeCoursey et al, 2003;Petheo and Demaurex, 2005), and its sustained production of superoxide requires the movement of a compensating charge, i.e., efflux of positively charged ions or influx of negatively charged ions. The translocation of electrons also generates opposite effects on the cytosolic and phagosomal pH.…”

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confidence: 99%

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

Chemaly¹,

Okochi²,

Sasaki³

et al. 2009

J Cell Biol

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Neutrophils kill microbes with reactive oxygen species generated by the NADPH oxidase, an enzyme which moves electrons across membranes. Voltage-gated proton channels (voltagesensing 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 2/2 mice lack proton currents but have normal electron currents, indicating that these cells have a fully functional oxidase that cannot conduct protons. VSOP/Hv1 2/2 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.

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“…Proton channels are opened by depolarization and/or cytoplasmic acidification and seem to be designed for rapid, efficient acid extrusion from cells (2). In phagocytes, they are thought to enable sustained NADPH oxidase activity by compensating for the electrogenic activity of the oxidase (3)(4)(5). Stimuli that activate NADPH oxidase in human eosinophils and neutrophils and in murine osteoclasts greatly enhance the opening of proton channels in these cells studied in perforated-patch configuration (6)(7)(8)(9)(10), largely via PKC phosphorylation (11).…”

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confidence: 99%

A pH-stabilizing role of voltage-gated proton channels in IgE-mediated activation of human basophils

Musset¹,

Morgan²,

Cherny³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Eosinophils and other phagocytes use NADPH oxidase to kill bacteria. Proton channels in human eosinophils and neutrophils are thought to sustain NADPH oxidase activity, and their opening is greatly enhanced by a variety of NADPH oxidase activators, including phorbol myristate acetate (PMA). In nonphagocytic cells that lack NADPH oxidase, no clear effect of PMA on proton channels has been reported. The basophil is a granulocyte that is developmentally closely related to the eosinophil but nevertheless does not express NADPH oxidase. Thus, one might expect that stimulating basophils with PMA would not affect proton currents. However, stimulation of human basophils in perforated-patch configuration with PMA, N-formyl-methionyl-leucyl-phenylalanine, or anti-IgE greatly enhanced proton currents, the latter suggesting involvement of proton channels during activation of basophils by allergens through their highly expressed IgE receptor (Fc RI). The anti-IgE-stimulated response occurred in a fraction of cells that varied among donors and was less profound than that to PMA. PKC inhibition reversed the activation of proton channels, and the proton channel response to anti-IgE or PMA persisted in Ca 2؉ -free solutions. Zn 2؉ at concentrations that inhibit proton current inhibited histamine release elicited by PMA or anti-IgE. Studied with confocal microscopy by using SNARF-AM and the shifted excitation and emission ratioing of fluorescence approach, anti-IgE produced acidification that was exacerbated in the presence of 100 M Zn 2؉ . Evidently, proton channels are active in basophils during IgE-mediated responses and prevent excessive acidification, which may account for their role in histamine release.asthma ͉ histamine ͉ patch-clamp ͉ HNVCN1 ͉ allergy

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The voltage dependence of NADPH oxidase reveals why phagocytes need proton channels

Cited by 294 publications

References 28 publications

TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons

TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons

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

A pH-stabilizing role of voltage-gated proton channels in IgE-mediated activation of human basophils

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