The sweeteners saccharin, D-tryptophan and neohesperidin dihydrochalcone (NHD), and the bitter tastant cyclo(Leu-Trp), stimulated concentration-dependent pigment aggregation in a Xenopus laevis melanophore cell line, similar to melatonin. Like melatonin, these tastants inhibited (by 45 to 92%) cAMP formation in melanophores; pertussis toxin pretreatment almost completely abolished the tastant-induced cAMP inhibition, suggesting the involvement of the inhibitory pathway (G_i) of adenylyl cyclase. The presence of luzindole (melatonin-receptor antagonist) almost completely abolished the inhibition of cAMP formation induced by saccharin, D-tryptophan and cyclo(Leu-Trp), but only slightly affected the inhibitory effect of NHD. In contrast, the presence of an ₂-adrenergic receptor antagonist, yohimbine, almost completely abolished the inhibition of cAMP formation induced by NHD, but had only a minor effect on that induced by the other tastants. Thus, saccharin, D-tryptophan and cyclo(Leu-Trp) are melatonin-receptor agonists whereas NHD is an ₂-adrenergic-receptor agonist, but both pathways lead to the same transduction output and cellular response. Formation of D-myo-inositol 1,4,5-trisphosphate (IP₃) in melanophores was reduced (15-58%, no concentration dependence) by saccharin, D-tryptophan and cyclo(Leu-Trp) stimulation, but increased by NHD stimulation. Tastant stimulation did not affect cGMP. Although some of the above tastants were found to be membrane-permeant, their direct activation of downstream transduction components in this experimental system is questionable. MT1 and MT2 melatonin receptor mRNAs were identified in rat circumvallate papilla taste buds and nonsensory epithelium suggesting the occurrence of MT1 and MT2 receptors in these tissues. Melatonin stimulation reduced the cellular content of cAMP in taste cells which may or may not be related to taste sensation.