Spatiotemporal orchestration of Ca2+-cAMP oscillations on AKAP/AC nanodomains is governed by an incoherent feedforward loop

The nanoscale organization of enzymes associated with the dynamics of second messengers is critical for ensuring compartmentation and localization of signaling molecules in cells. Specifically, the spatiotemporal orchestration of cAMP and Ca 2+ oscillations is critical for many cellular functions. Previous experimental studies have shown that the formation of nanodomains of A-kinase anchoring protein 79/150 (AKAP150) and adenylyl cyclase 8 (AC8) on the surface of pancreatic MIN6 β cells modulates the phase of Ca 2+ -cAMP oscillations from out-of-phase to in-phase. In this work, we develop computational models of the Ca 2+ /cAMP pathway and AKAP/AC nanodomain formation that give rise to the two important predictions: instead of an arbitrary phase difference, the out-of-phase Ca 2+ /cAMP oscillation reaches Ca 2+ trough and cAMP peak simultaneously, which is defined as inversely out-of-phase; the in-phase and inversely out-of-phase oscillations associated with Ca 2+ -cAMP dynamics on and away from the nanodomains can be explained by an incoherent feedforward loop. Factors such as cellular surface-to-volume ratio, compartment size, and distance between nan-odomains do not affect the existence of in-phase or inversely out-of-phase Ca 2+ /cAMP oscillation, but cellular surface-to-volume ratio and compartment size can affect the time delay for the inversely out-of-phase Ca 2+ /cAMP oscillation while the distance between two nanodomains does not. Finally, we predict that both the Turing pattern-generated nanodomains and experimentally measured nan-odomains demonstrate the existence of in-phase and inversely out-of-phase Ca 2+ /cAMP oscillation when the AC8 is at a low level, consistent with the behavior of an incoherent feedforward loop. These findings unveil the key circuit motif that governs cAMP and Ca 2+ oscillations and advance our understanding of how nanodomains can lead to spatial compartmentation of second messengers.