Nonlinear dynamics in phosphoinositide metabolism

Phosphoinositides broadly impact membrane dynamics, signal transduction and cellular physiology. The orchestration of signaling complexity by this seemingly simple metabolic pathway remains an open question. It is increasingly evident that comprehending the complexity of the phosphoinositides metabolic network requires a systems view based on nonlinear dynamics, where the products of metabolism can either positively or negatively modulate enzymatic function. These feedback and feedforward loops may be paradoxical, leading to counterintuitive effects. In this review, we introduce the framework of nonlinear dynamics, emphasizing distinct dynamical regimes such as the excitable state, oscillations, and mixed-mode oscillations—all of which have been experimentally observed in phosphoinositide metabolisms. We delve into how these dynamical behaviors arise from one or multiple network motifs, including positive and negative feedback loops, coherent and incoherent feedforward loops. We explore the current understanding of the molecular circuits responsible for these behaviors. While mapping these circuits presents both conceptual and experimental challenges, redefining cellular behavior based on dynamical state, lipid fluxes, time delay, and network topology is likely essential for a comprehensive understanding of this fundamental metabolic network.