Reactive oxygen species–AMP-activated protein kinase–Protein kinase C zeta–Sodium-potassium adenosine triphosphatase signaling pathway (ROS–AMPK–PKCζ–Na,K-ATPase pathway)

The ROS–AMPK–PKCζ signaling pathway is a specialized regulatory axis that mediates the downregulation of the Sodium-potassium adenosine triphosphatase (Na,K-ATPase) at the plasma membrane of alveolar epithelial cells in response to low oxygen levels. Under hypoxic conditions, an increase in mitochondrial-derived reactive oxygen species (ROS) triggers the activation of AMP-activated protein kinase (AMPK), which in turn activates the atypical protein kinase C isoform, PKCζ. Once activated, PKCζ phosphorylates the alpha-subunit of the Na,K-ATPase, providing a signal for its internalization from the cell surface into intracellular clathrin-coated vesicles. This endocytic process reduces the number of active sodium pumps available for ion transport, leading to impaired alveolar fluid clearance and the subsequent development of pulmonary edema. This pathway is a significant focus in respiratory research, as pharmacological intervention to stabilize Na,K-ATPase at the membrane could provide therapeutic benefits for patients with acute lung injury or high-altitude sickness.

Other names

Hypoxia-induced Na,K-ATPase endocytosis pathwayROS-mediated Na,K-ATPase regulationAMPK-PKCζ-Na,K-ATPase axisAlveolar epithelial Na,K-ATPase downregulation pathway

Modulation of this pathway involves the use of antioxidants to scavenge ROS, AMPK inhibitors or activators to regulate the metabolic trigger, or specific PKCζ inhibitors to prevent the phosphorylation and subsequent clathrin-mediated endocytosis of the Na,K-ATPase alpha-subunit.