(a) Impulse response of plasma membrane cAMP (blue) to a spike in Ca2+ entry (black), triggered by KCl-mediated membrane depolarization (wash in/out). The transient decrease in PM-cAMP is coupled to the transient increase in intracellular Ca2+. (b) Acute inhibition of Ca2+-sensitive PDE1 decouples the out-of-phase PM-cAMP oscillations from Ca2+ oscillations, as observed in this representative cell trace (Ca2+ – black, PM-cAMP – blue). (c) The oscillatory phase of cAMP can be manipulated by tuning the relative activity of Ca2+-sensitive PDE and AC, as demonstrated by a simplified mathematical model. The schematic shows the network architecture. The relative activities of AC and PDE, denoted as v(AC) and v(PDE), control the delay between Ca2+ and cAMP. Point (i), with high AC activity and low PDE, shows in phase oscillations of Ca2+ and cAMP, whereas point (ii), with high PDE and low AC activity shows out of phase oscillations. These dynamics are shown in the line graphs. (d) Knocking down AC8 is correlated with an increase in the time lag for oscillatory cAMP at the AKAP79/150 microdomain (37 ± 9 s, n = 11), indicating more cells exhibiting out-of-phase cAMP oscillations (representative cell trace, Ca2+ – black, AKAP79/150-cAMP – red). (e) Over-expressing AC8 is sufficient to reverse the phase at the PM to in-phase (23 ± 2 s, n = 56) (representative cell trace, Ca2+ – black, PM cAMP – blue). **p=0.0014, ****p<0.0001; unpaired two-tailed Student’s t-test.