Current understanding of ENaC regulation by P2Y2/PLC/PI(4,5)P2 pathway.

The epithelial sodium channel (ENaC) localized in the cell membrane is crucial for sodium transport and blood pressure regulation. Discovered in frog skin, ENaC is expressed in the colon, lungs, exocrine glands, and most notably in the distal nephron of the kidneys, where it limits sodium reabsorption. Mutations in ENaC cause hereditary hypertension (Liddle's syndrome) or hypotension (pseudohypoaldosteronism type 1). ENaC activity and expression are tightly controlled by various signaling molecules and second messengers. For example, urinary ATP binding to the P2Y2 receptor inhibits ENaC. ENaC also interacts with PI(4,5)P2 and the ubiquitin ligase Nedd4-2 via specific motifs. PI(4,5)P2 is essential for ENaC stability, trafficking, and gating. This review focuses on the regulatory roles of the P2Y2 receptor and PI(4,5)P2 on ENaC regulation.