Binding of cAMP and adenosine derivatives to Dictyostelium discoideum cells. Relationships of binding, chemotactic, and antagonistic activities.

Dictyostelium discoideum cells contain one class of cAMP receptors and two classes of adenosine receptors (respectively, adenosine alpha- and beta-receptors). A cell has 3.5 X 10(4) adenosine alpha-receptors with a Kd = 0.8 microM and 8 X 10(6) adenosine beta-receptors with a Kd = 350 microM. Binding of adenosine to the beta-receptors inhibits up to 90% of the binding of cAMP to the cAMP receptors in a noncompetitive way. Measurement of the chemotactic and antagonistic activity of 18 cAMP and adenosine derivatives for aggregative D. discoideum cells resulted in four functional groups. 1) Nine compounds are full agonists; they are chemotactic but have no antagonistic effects on the chemotactic activity of cAMP. 2) Five compounds are partial antagonists; they can be both agonists as well as antagonists, depending on the concentration used. 3) Two compounds are competitive full antagonists, and 4) three compounds are noncompetitive full antagonists. Comparison of the quantitative data on the chemotactic and antagonistic activities of all compounds with their binding data for cAMP and adenosine cell surface receptors leads to the following conclusions on the mechanism of action of the antagonists. The two competitive full antagonists bind to the cAMP receptor, but they do not activate the receptor; therefore, they do not induce a response, and at the same time prevent the detection of cAMP. The three noncompetitive antagonists bind to the adenosine beta-receptor which inhibits the binding of cAMP to the cAMP receptor; also these compounds prevent the detection of cAMP. The five competitive partial antagonists bind to the cAMP receptor and induce a normal cGMP response. Also cAMP induces a normal cGMP response in the presence of partial antagonists. This indicates that partial antagonists do not prevent the detection of cAMP, but extinguish the intracellular response to cAMP. A model is presented for the mechanism of action of these partial antagonists which is based on false reading of chemotactic signals in terms of excitation and adaptation processes.