A MODEL FOR CAMP-MEDIATED CGMP RESPONSE IN DICTYOSTELIUM-DISCOIDEUM

In Dictyostelium discoideum extracellular cyclic AMP (cAMP), as shown by previous studies, induces a transient accumulation of intracellular cyclic guanosine-5'-monophosphate (cGMP), which peaks at 10 s and rec overs basal levels at 30 s after stimulation, even with persistent cAM P stimulation. Additional investigations have shown that the cAMP-medi ated cGMP response is built up from surface cAMP receptor-mediated act ivation of guanylyl cyclase and hydrolysis of cGMP by phosphodiesteras e. The regulation of these activities was measured in detail on a seco nds time-scale, demonstrating complex adaptation of the receptor, allo steric activation of cGMP-phosphodiesterase by cGMP, and potent inhibi tion of guanylyl cyclase by Ca2+. In this paper we present a computer model that combines all experimental data on the cGMP response. The mo del is used to investigate the contribution of each structural and reg ulatory component in the final cGMP response. Four models for the acti vation and adaptation of the receptor are compared with experimental o bservations. Only one model describes the magnitude and kinetics of th e response accurately. The effect of Ca2+ on the cGMP response is simu lated by changing the Ca2+ concentrations outside the cell (Ca2+ influ x) and in stores (IP3-mediated release) and changing phospholipase C a ctivity. The simulations show that Ca2+ mainly determines the magnitud e of the cCMP accumulation; simulations are in good agreement with exp eriments on the effect of Ca2+ in electropermeabilized cells. Finally, when cGMP-phosphodiesterase activity is deleted from the model, the s imulated cGMP response is elevated and prolonged, which is in close ag reement with the experimental observations in mutant stmF that lacks t his enzyme activity. We conclude that the computer model provides a go od description of the observed response, suggesting that the main stru ctural and regulatory components have been identified.