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

Abstract

AbstractThe 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 Ca2+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 Ca2+-cAMP oscillations. In this work, we develop computational models of the Ca2+/cAMP pathway and AKAP/AC nanodomain formation that give rise to two important predictions: first, the in-phase and out-of-phase oscillations associated with Ca2+-cAMP dynamics on and away from the nanodomains can be explained by an incoherent feedforward loop. Second, the formation of these nanodomains can be explained by Turing patterns. Factors such as cellular surface-to-volume ratio, compartment size, and distance between nanodomains do not affect the existence of in-phase or perfectly out-of-phase Ca2+/cAMP oscillation, but some of these factors can affect the time delay for the perfectly out-of-phase Ca2+/cAMP oscillation. Finally, we predict that both the Turing pattern-generated nanodomains and experimentally measured nanodomains demonstrate the existence of in-phase and perfectly out-of-phase Ca2+/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 Ca2+oscillations and advance our understanding of how nanodomains can lead to spatial compartmentation of second messengers.