Emergence of Irreversibility in Simple Signaling Modules

Abstract ID 91135 Poster Board 030 Bistability in signaling modules, vital in systems biology and pharmacology, is crucial for understanding cellular decision-making and irreversibility in signaling processes. Governing various cellular functions, signaling pathways often exhibit complex dynamics like bistability, where a system maintains two stable states. This characteristic is essential in understanding how cells make 'decisions' and maintain these decisions in order to adapt when faced with fluctuating external conditions. Developing simplified models of bistable signaling modules helps in comprehending and modeling irreversible cellular processes and in simplifying complex biological signaling networks. Traditionally, bistability studies focus on systems transitioning irreversibly post exposure to a significant event. Less attention has been given to mechanisms leading to irreversibility from repeated, weaker events or prolonged low-level exposures. Current standard models, describing immediate responses to signals exceeding critical thresholds, lack the capacity to account for irreversibility induced by repeated or chronic sub-critical exposures. In order to model this phenomenon, our hypothesis introduces a slowly degrading precursor, secondary to a driving signal (like a drug), that mediates the self-regulatory induction of a biosignal by acting as an enhancer of the positive feedback. At repeated, low signal levels, this precursor slowly accumulates and promotes the accumulation of the biosignal, which drives the transition between steady states. Similarly, our hypothesis demonstrates how chronic exposure leading to long-term accumulation of intermediates can trigger an irreversible transition, despite consistently low external signal levels. In this case, a slight modification of the repeated dosing, with an appropriate adjustment in the kinetic disposition of the precursor, is warranted. Provided that the cascade's output is regulated ultra-sensitively, the system will exhibit an abrupt transition at a critical level of the biosignal, accumulated over time. In conclusion, our indirect response models effectively capture the dynamics of irreversible transitions in signaling molecules. While current models demonstrate bistability induced from a single, above-threshold stimulus, our model demonstrates an alternative mechanism where bistability is induced from repeated or chronic low-level stimuli. These models pave the way for advanced models describing long-term physiological changes, offering insights into cellular responses to fluctuating or prolonged stimuli and highlighting the nature of cellular decision-making processes. IPA acknowledges support from NIH131800. KN acknowledges support from NIH7R25ES020721-13.