A unified framework to model gap-junction dynamics during the growth–quiescence cycle

Understanding gap-junction remodelling during the growth–quiescence cycle in regenerating epithelia is crucial yet remains contentious. The junctional homeostasis hypothesis (JHH) proposes conductance down-scaling during the quiescent phase, whereas other studies describe conductance potentiation, or phase-specific shifts, contingent on bioelectric activity expressed during growth. To delineate boundary conditions between these divergent observations, we focused on connexin-gating rules and transmembrane voltage patterns that shape junctional dynamics. Using computational models parameterised with mammalian epithelial progenitors, we discovered that under coincidence-based connexin gating and voltage-timing dependent plasticity (VTDP), growth-like voltage patterns lowered junctional conductance, whereas quiescence-like patterns enhanced conductance. We term this phenomenon Growth Inhibition and Quiescence Excitation (GIQE). Conversely, when anti-coincidence and anti-VTDP rules were applied, conductance depression arose during the quiescent phase, in agreement with the conventional junctional homeostasis hypothesis. Furthermore, the magnitude and direction of remodelling were governed by differences in membrane-potential fluctuation rates between quiescence and growth. We therefore present a unified framework capable of reconciling junctional homeodynamics across the growth–quiescence cycle.