Figure 9.

Model of periodic activation and adaptation of cAR1-mediated responses and proposed mechanism of DN mutant dominant-negative activity. (A) cAR1 is normally stimulated by cAMP waves every 6 min, triggering the excitation of multiple Gα2βγ (“G” in figure)-dependent as well as multiple G protein-independent pathways (depicted by single arrows for clarity), which collectively result in cAMP relay, chemotaxis, and pulse-induced gene expression (left). The latter is depicted for Gα2 (dashed line). After a delay, inhibitory signals (flat-headed curved arrows) from cAR1 block transmission of the excitatory signal, resulting in adaptation (right). PDE-mediated cAMP hydrolysis initiates deadaptation, allowing the cell to respond to the next cAMP wave. (B) The dominant-negative mutants described are proposed to be constitutively activated (cAR1^*) and as such are expected to cause persistent adaptation, thereby interfering with pulse-induced gene expression, cAMP relay, and chemotaxis. Failure to express high levels of Gα2 due to impaired pulse-induced gene expression would contribute to the impairment of cAMP relay, chemotaxis, and other Gα2-mediated processes required for aggregation and development. See text for additional details.