2-Deaminofolic acid elicits desensitization without excitation of the cyclic GMP response in Dictyostelium discoideum

Folic acid induces a rapid transient increase in cellular cGMP levels in D. discoideum. A half-maximal cGMP response is effected by about 0.2 μM folate. In addition, extracellular folate is rapidly inactivated by deaminases. The main product 2-deaminofolic acid generates no measurable cGMP response at concentrations of up to 0.1 mM. At 1 mM a 10% response is observed. In contrast, 1 mM deaminofolic acid inhibits the cGMP accumulation as induced by 0.3 μM folic acid by 90%. This antagonism by deaminofolate is competitive with a K_I value of 20 μM. When the cells are preincubated with deaminofolic acid before stimulation with folic acid, the inhibition changes to a non-competitive type (K_I = 20 μM). It is concluded that although deaminofolate does not elicit cGMP accumulation, some cellular process is activated resulting in a diminished cGMP response to saturating folate stimuli. This process of desensitization is characterized by a first-order rate constant of 0.04 s⁻¹, while folic acid-induced desensitization proceeds with a higher rate of 0.6 s⁻¹. We discuss that the latter rate constant is more likely to reflect the rate of detection of a desensitizing signal, rather than the rate of the desensitization process itself.