The poorly differentiated human gastric carcinoma cell line MKN-45 possesses histamine H2 receptors, which are linked to stimulation of adenosine 3',5'-cyclic monophosphate (cAMP) production. Pretreatment of MKN-45 cells with histamine elicited a rapid and dose-dependent inhibition of cAMP production in response to subsequent administration of histamine, whereas pretreatment with prostaglandin E2 (PGE2) or forskolin, both of which stimulate cAMP formation in these cells, had no effect on the histamine-induced cAMP production. Neither NaF- nor forskolin-induced cAMP production was affected by histamine pretreatment. Scatchard analysis of data obtained for [3H]-tiotidine binding showed that histamine pretreatment affected neither the number of histamine H2 receptors nor the binding affinity of the ligand for the receptors. Finally, histamine pretreatment had no effect on cAMP response to subsequent addition of PGE2, which was reduced by PGE2 pretreatment. These results suggest that histamine induces homologous desensitization of H2 receptors on MKN-45 cells by a mechanism that does not involve stimulation of cAMP production.