Hormone oscillations preserve responsiveness and cross-cell-type coordination of endocrine signaling

Abstract

Living organisms continuously adapt to changing physiological demands by sensing fluctuating concentrations of hormones. This requires hormone signaling pathways to remain responsive over time and discriminate differences in concentration. However, sustained exposure to hormones induces desensitization, which safeguards against overstimulation but may impair cells ability to sense future changes in hormone. How the endocrine system circumvents this paradox to preserve responsiveness remains unresolved. Here, using epinephrine-mediated stress signaling as a model, we show that natural ultradian hormone oscillations provide a solution. Oscillatory exposure permits receptor resensitization when hormone levels fall, thereby preserving cellular alertness to future stress and tunability across stimulus intensities. Oscillation also maintains coordination of alertness across diverse cell types by buffering against cell-type variation in receptor kinetics. Ultradian oscillations thus enable endocrine systems to retain protective desensitization while preserving responsiveness and cross-cell-type coordination. Our findings suggest hormone therapies should leverage temporal dynamics to avoid drug-induced tolerance.