Model of activation of the phagocyte Nox2 NADPH oxidase. In the unstimulated neutrophil, cytosolic p47phox, p67phox, and p40phox exist as a cytosolic complex. The other cytosolic regulator, Rac2 GTPase, exists in its GDP-bound (inactive) form as a separate complex with Rho GDP dissociation inhibitor (RhoGDI). On activation of the neutrophil, Rac2 is released from GDI, translocates to the membrane, and nucleotide exchange occurs. Also during activation, p47phox is phosphorylated on multiple serines, leading to the translocation of the p47/p67/(p40?) complex to the membrane; this event is distinct from the translocation of Rac GTPase. At the membrane, the cytosolic components interact with cytochrome b558, which is composed of two subunits, Nox2 (or gp91phox) and p22phox. Nox2 contains the binding site for NADPH, FAD, and two heme groups. The interaction of the cytosolic components with Nox2 allows electrons to flow from cytoplasmic NADPH to cytochrome b558-bound FAD (Step 1) to the heme groups, and finally to the heme-bound oxygen to form superoxide anion (Step 2) on the external side of the plasma membrane. See text for details.