Department of Cell Biology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520-8002, USA.
Department of Physics, Yale University, New Haven, CT, 06511, USA.
Curr Opin Cell Biol. 2024 Jun;88:102373. doi: 10.1016/j.ceb.2024.102373. Epub 2024 May 25.
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.
磷脂酰肌醇广泛影响膜动力学、信号转导和细胞生理学。这种看似简单的代谢途径对信号复杂性的协调仍然是一个悬而未决的问题。越来越明显的是，要理解磷脂酰肌醇代谢网络的复杂性，需要基于非线性动力学的系统观点，其中代谢产物可以正向或负向调节酶的功能。这些反馈和前馈回路可能是矛盾的，导致违反直觉的效果。在这篇综述中，我们介绍了非线性动力学的框架，强调了不同的动力学状态，如兴奋状态、振荡和混合模式振荡——所有这些在磷脂代谢中都有实验观察到。我们深入探讨了这些动力学行为是如何由一个或多个网络基序产生的，包括正反馈回路和负反馈回路、相干和非相干前馈回路。我们探讨了目前对这些行为负责的分子回路的理解。虽然映射这些回路既具有概念性又具有实验性挑战，但基于动力学状态、脂质通量、时滞和网络拓扑重新定义细胞行为，对于全面理解这个基本代谢网络可能是必不可少的。
