Feed-forward model of PKA activation. (a) Double-negative feedback loop. In the resting state, Cα is inhibited by RIIα. However, once Cα is activated by cAMP it is able to phosphorylate RIIα at Ser-99, which prevents RIIα from inhibiting Cα. (b) Illustration of the feedback mechanism occurring within a hypothetical trimeric AKAP complex. AKAP (light blue helix) recruits PKA (R homodimer, orange; C, light yellow) to a membrane associated target X (red). In the context of this AKAP oligomer, activation of a single Cα is likely to phosphorylate RIIα within the complex leading the release of further Cα. This process increases the probability that all Cα within the complex will become active as each additional Cα is activated. The increased amount of active Cα also increases the probability of target phosphorylation.