Developmental regulation of the pathways of folate-receptor-mediated stimulation of cAMP and cGMP synthesis in Dictyostelium discoideum

Recently, we demonstrated the presence of multiple folate-binding sites on the cell surface of Dictyostelium discoideum. These sites were divided into two major classes, with different ligand specificities (A and B). Each major class consists of several interconvertible subtypes. In the present report, the ability of 13 folate analogs to activate both adenylate and guanylate cyclase in pre- as well as postaggregative cells is examined. The patterns of correlation between binding and activation data indicate that guanylate cyclase activation is mediated by the B-sites in both developmental stages (P less than 0.001). In postaggregative cells, adenylate cyclase also seems to be activated by the B-sites (P less than 0.001). In contrast, adenylate cyclase activation in preaggregative cells was well correlated with the specificity of A-sites (P less than 0.01). Remarkably, the potencies of activation were less affected by molecular modifications than the binding affinities were, as suggested by a slope of 0.4 in a plot of K0.5 values of activation vs. binding. This observation argues against the existence of a transduction mechanism in which the response is proportional to receptor occupancy. For the B-receptor, however, the degree of receptor occupancy appears to determine the response. The existence of folic acid antagonists is demonstrated, some of which are specific for either A-sites coupled to adenylate cyclase or for B-sites coupled to guanylate cyclase.