A unified framework to model gap-junctional dynamics across the growth–quiescence cycle

Understanding gap-junctional dynamics across the growth–quiescence cycle in epithelia is crucial yet remains controversial. The junctional homeostasis hypothesis (JHH) proposes coupling depression during the quiescent phase, whereas other studies report potentiation or phase-specific changes that depend on ionic activity during growth. To identify boundary conditions between these contradictory observations, we focused on plasticity rules and bioelectric patterns that govern junctional conductance. Using computational models of mammalian epithelial cells, we found that under coactivity-dependent coupling plasticity (CDCP) and voltage-timing dependent plasticity (VTDP), growth-like bioelectric patterns decreased gap-junctional conductance, whereas quiescence-like patterns strengthened it. We term this tendency Growth Inhibition and Quiescence Excitation (GIQE). Conversely, under inverse-CDCP and inverse-VTDP, coupling depression during quiescence was observed, in agreement with the conventional junctional homeostasis hypothesis. Moreover, the magnitude and direction of conductance change depended on differences in membrane potential fluctuations between quiescence and growth phases. We provide a unified framework that can account for gap-junctional homeodynamics across the growth–quiescence cycle.