Because G protein-regulated cation channels in type II pneumocytes constitute the most likely pathway for alveolar Na⁺ entry, we explored the hypothesis that a G protein-coupled prostaglandin (PG) E₂ receptor controls perinatal lung alveolar Na⁺ transport. [³H]PGE₂ binding to the alveolar apical membrane was trypsin sensitive and showed a rank order of competitive inhibition: PGE₂ = PGE₁ > PGD₂ > PGF₂. Kinetic analysis demonstrated both high-affinity [dissociation constant (K_D) = 2.1 ± 0.7 nM; maximal binding (B_max) = 27 ± 7 fmol/mg protein] and low-affinity (K_D = 28 ± 2 nM; B_max = 265 ± 29 fmol/mg protein) binding sites. Modulation of high-affinity GTPase activity identified a similar potency order (IC₅₀ = 11 mM for PGF₂ vs. 10-50 µM for other PGs), suggesting that the receptors are G protein coupled. Finally, 1 µM PGE₂ (IC₂₅) increased conductive ²²Na⁺ uptake into membrane vesicles only in the presence of 100 µM intravesicular GTP. The K_D value for the high-affinity binding site together with the rank order of PG effect on ligand binding and G protein function places this PG receptor in the EP₃ subtype, whereas Na⁺ uptake studies suggest that it helps maintain perinatal lung Na⁺ homeostasis.