Abnormal activation of H+ conductance in NADPH oxidase-defective neutrophils.
To combat bacterial infection, phagocytes generate superoxide (O2-) and other microbicidal oxygen radicals. NADPH oxidase, the enzyme responsible for O2- synthesis, is deficient in chronic granulomatous disease (CGD) patients. Although O2- generation is accompanied by a large burst of metabolic acid production, intracellular pH (pHi) remains near neutrality due to the concomitant stimulation of H+ extrusion. Three major pathways contribute to pHi regulation in activated phagocytes: Na+/H+ exchange, vacuolar-type H+ pumps, and a H+ conductance. The present study analyzed the relationship between activation of the NADPH oxidase and stimulation of the H+ extrusion mechanisms in human blood neutrophils. Phorbol ester-induced activation of Na+/H+ exchange and H+ pumping occurred normally in cells from CGD patients. Unlike normal individuals, however, CGD patients were unable to activate the H+ conductive pathway. Thus, activation of the H+ conductance appears to be contingent on the assembly of a functional NADPH oxidase. These findings imply a dual role of the NADPH oxidase in O2- synthesis and in the regulation of pHi. The oxidase (or some components thereof) may itself undertake H+ translocation or, alternatively, may signal the activation of a separate H+ conducting entity.[1]References
- Abnormal activation of H+ conductance in NADPH oxidase-defective neutrophils. Nanda, A., Grinstein, S., Curnutte, J.T. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
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