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(Journal of Leukocyte Biology. 2002;71:611-617.)
© 2002 by Society for Leukocyte Biology

Capacitative Ca²⁺ influx and activation of the neutrophil respiratory burst. Different regulation of plasma membrane- and granule-localized NADPH-oxidase

Daniel Granfeldt^*, Marie Samuelsson and Anna Karlsson^*

The Phagocyte Research Laboratory, Departments of
^* Rheumatology, and
Medical Microbiology and Immunology, University of Göteborg, Sweden

Correspondence: Anna Karlsson, The Phagocyte Research Laboratory, Department of Rheumatology, Guldhedsgatan 10, S-413 46 Göteborg, Sweden. E-mail: anna.karlsson{at}microbio.gu.se

The neutrophil NADPH-oxidase may be activated in the plasma membrane, resulting in release of oxygen metabolites extracellularly, or in the granule or phagosomal membranes, giving intracellular production of oxidants. An increase in [Ca²⁺]_i mediated through binding of fMLF to its receptor is part of a signaling cascade that activates the plasma membrane-localized oxidase. In contrast, a rise in [Ca²⁺]_i induced by a Ca²⁺ ionophore results in activation of the intracellular pool of oxidase. We mimicked fMLF-induced emptying of intracellular Ca²⁺ stores with thapsigargin. This induced a pronounced intracellular oxidase activity but no extracellular release of oxidants. The thapsigargin-induced effect was dependent on capacitative Ca²⁺ influx, because the effect was inhibited dose-dependently by EGTA and the Ca²⁺ channel blocker La³⁺. At La³⁺ concentrations between 200 and 400 µM, thapsigargin also induced a massive extracellular production of superoxide anion. No other channel blockers tested induced a similar effect. We conclude that elevation in [Ca²⁺]_i by capacitative Ca²⁺ influx induces NADPH-oxidase activation at an intracellular site. Further, activation of the plasma membrane-localized NADPH-oxidase is regulated by a more complex Ca²⁺ signaling, involving capacitative Ca²⁺ influx and possibly the specific action of La³⁺-sensitive Ca²⁺ channels.

Key Words: thapsigargin • signal transduction • fMLF • [Ca⁺⁺]_i

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