FIGURE 6: Regulation of endocytosis by oxygen stress. Under adequate oxygen supply there is limited endocytosis of the Na⁺/K⁺-ATPase, which is needed at the plasma membrane to build up the ion gradient that supports alveolar fluid clearance. When oxygen levels drop, the endocytosis of Na⁺/K⁺-ATPase is promoted to preserve energy. Hypoxia-induced ROS via an increase in Ca²⁺ lead to the activation of CAMKK-β which activates AMPK and PKC-ζ. PKC-γ phosphorylates sites on AP-2 and the Na⁺/K⁺-ATPase to boost Na⁺/K⁺-ATPase endocytosis. During prolonged hypoxia, the HIF pathway triggers the ubiquitination and degradation of PKC-ζ by elevating the expression of the E3 ubiquitin ligase HOIL-1L. In this way cells balance energy preservation and alveolar fluid clearance for cellular and organismal survival (see section ”Hypoxia – O₂ stress” for further details).