FIGURE 8.

The inhibition of epithelial sodium channel (ENaC) open probability (P_o) by dietary salt is mediated by the ATP/UTP/Cx30/P2Y₂ receptor system in the aldosterone-sensitive distal nephron. Low salt intake enhances aldosterone concentrations and suppresses apical release of ATP and UTP. This reduces activation of apical P2Y₂ receptors on principal cells (PC), and the inner leaflet of the lipid bilayer maintains a high concentration of negatively charged phosphatidylinositol 4,5-bisphosphate (PIP₂), which binds to positively charged domains of the NH₂ terminus of the β-subunit of ENaC, thereby keeping the ENaC channel open to reabsorb Na⁺. High salt intake enhances the apical release of ATP and UTP, at least in part via connexin30 (Cx30) in intercalated cells (IC). The nucleotides activate P2Y₂ receptors and, thereby, phospholipase C (PLC), which hydrolyzes and lowers the concentration of negatively charged PIP₂. This releases the NH₂ terminus of β-ENaC and induces a conformation change that lowers ENaC P_o and activity, thereby increasing Na⁺ excretion. See text for details. IP₃, inositol trisphosphate. [Modified from Vallon and Rieg (527).]