The adenylate cyclase system of human fundic gastric mucosa was found to respond to histamine, prostaglandin E 2 and the non-hormonal activators NaF and 5'-guanylyl-imidodiphosphate (GMP(PNP)). Half maximal stimulation of enzyme activity was observed at a histamine concentration of 50 micrometer. Maximal stimulation (about 25%) occurred at a histamine concentration of 1 mM. The stimulatory effect of histamine was competitively inhibited by cimetidine. The stimulatory effect of prostaglandin E 2 was found to be dose-dependent over a concentration range from 0.1 micrometer to 1 mM exerting maximal effects at 0.3 mM. NaF and GMP(PNP) by inducing an about 3.5-fold increase of enzyme activity were more potent in stimulating the human enzyme system than histamine and prostaglandin E 2. Maximal stimulatory doses of prostaglandin E 2 and histamine had an additive effect on the adenylate cyclase activity from fundic gastric mucosa. This implies that histamine acts on an individual adenylate cyclase system. Our results are suggestive for the existence of an adenylate cyclase system in human gastric mucosa coupled to histamine H 2-receptor sites.