Prostaglandin (PG) receptors are present on enzymatically dissociated cells from the rat renal medulla and are subject to homologous regulation both in vivo and in vitro. One hour after injection of 100 micrograms of 16,16'-dimethyl-PGE2, the number of PGE2 binding sites on renal cells declines to 40% of controls. In vitro exposure of renal cells to PGE2 or dimethyl-PGE2 also results in a time- and concentration-dependent "down" regulation of prostaglandin receptors. In the absence of indomethacin in the incubation medium, endogenously synthesized prostaglandins mediate a similar time-dependent loss of cell-associated receptors. This loss is reversible since, after agonist removal and reincubation of the cells at 37 degrees C, there is a rapid (within 15 min) reappearance of PGE2 receptors (to 60-93% of controls). Reappearance occurs whether down regulation is induced in vitro by endogenously synthesized prostaglandins, added PGE2 or dimethyl-PGE2, or in vivo after injection of dimethyl-PGE2. Cycloheximide does not affect down regulation but significantly prevents subsequent recovery of the receptors. In contrast, neither colchicine nor chloroquine influences homologous regulation of renal prostaglandin receptors. These results document an agonist-induced reversible cycling of renal prostaglandin receptors which may determine the effectiveness of prostaglandin action in normal and pathologic states.