There are at least four subtypes of prostaglandin E (PGE) receptors. The EP1 and EP3 receptors are coupled to Ca2+ mobilization and the inhibition of adenylate cyclase, respectively, and the EP2 and EP4 receptors are coupled to the same signal transduction pathway, stimulation of adenylate cyclase. To identify the functional differences between EP2 and EP4 receptors, we examined agonist-induced desensitization of these two receptors using Chinese hamster ovary cells, which stably express these receptors. The EP4 receptor underwent short term agonist-induced desensitization, but no such desensitization was observed for the EP2 receptor. In contrast, the EP2 and EP4 receptors displayed similar patterns of down-regulation in response to prolonged exposure to PGE2. On the other hand, PGE2 is rapidly metabolized to 15-keto-PGE2 and, subsequently, to 13,14-dihydro-15-keto-PGE2. Thus, we compared the sensitivities of the two receptors to these two metabolites. The EP4 receptor markedly lost the response at the first metabolism, whereas the EP2 receptor gradually lost the response according to the degree of metabolism, having higher sensitivity to the first metabolite, 15-keto-PGE2, than the EP4 receptor. Therefore, the physiological significance of EP2 and EP4 may lie in their different sensitivities to agonist-induced short term desensitization and their differential susceptibilities to the metabolic inactivation of the agonist.