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J. Biol. Chem., Vol. 269, Issue 44, 27280-27285, 11, 1994
A Nanda, R Romanek, JT Curnutte and S Grinstein
Phagocytic cells can kill microorganisms by synthesizing superoxide.
Activation of the NADPH oxidase that generates superoxide is accompanied by
a large intracellular burst of metabolic acid production. Despite the
excess acid generation, cytosolic pH (pHi) remains near neutrality due to
the concomitant stimulation of several homeostatic H+ extrusion mechanisms
including a recently described H(+)- conductive pathway. Activation of the
conductance by phorbol esters is defective in neutrophils of chronic
granulomatous disease (CGD) patients lacking the transmembrane cytochrome b
subunits of the NADPH oxidase. This finding suggests that the oxidase
itself undertakes H+ translocation or that, alternatively, assembly of the
oxidase is required to activate a separate H+ conducting entity. To
distinguish between these possibilities, the presence of the conductive
pathway was assessed in unstimulated normal and CGD cells by manipulating
pHi and the transmembrane potential. Using fluorimetric determinations of
pHi, a conductive, Zn(2+)-sensitive alkalinization was observed in
neutrophils from both normal and cytochrome b-deficient CGD donors. The
electrophysiological properties of the conductance were defined in purified
blood monocytes using the whole cell configuration of the patch clamp.
Depolarizing pulses induced slowly activating outward currents in cells
from both normal and cytochrome b-deficient individuals. The elicited
currents were potentiated by cytosolic acidification and did not inactivate
within the times tested. As in control leukocytes, the reversal potential
of tail currents in the CGD cells closely approximated the H+ equilibrium
potential and was unaffected by substitution of the major ionic components
of the external bathing medium. At all voltages tested, the magnitude of
the evoked currents was comparable in normal and CGD cells. The results
indicate that, like macrophages and granulocytes, human monocytes display a
voltage-gated highly H(+)-selective conductance. More importantly, our
findings imply that the conductive pathway is present in cells devoid of
cytochrome b. Therefore, the defective activation of the conductive pathway
by protein kinase C agonists in CGD cells is not due to the physical
absence of the transporter. Instead we propose that the oxidase functions
in a regulatory capacity, facilitating the opening of a distinct H+
conductance during cellular stimulation.
Assessment of the contribution of the cytochrome b moiety of the NADPH oxidase to the transmembrane H+ conductance of leukocytes
Division of Cell Biology, Research Institute, Hospital for Sick Children, Toronto, Canada.
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