Receptor polarization through localized activity and global sensitization

Abstract

Directional sensing enables eukaryotic cells to detect spatial gradients of extracellular ligands by comparing local signaling activity to an internal set point. While this capability is typically attributed to signaling pathways downstream of cell surface receptors, we present a reaction-diffusion model to argue that receptors themselves can perform directional sensing via a mechanism we term Localized Activity and Global Sensitization (LAGS). LAGS integrates common receptor signaling motifs: lateral diffusion, basal activity, and active receptor degradation. Without diffusion, receptor activity locally adapts to a ligand-independent set point via degradation-mediated integral feedback, leading to receptor depletion in ligand-rich regions. The introduction of lateral diffusion redistributes primarily ligand-free receptors across the cell surface, creating a spatial mismatch between local activity and feedback. This mismatch drives polarized receptor activity relative to the set point, while rapid ligand equilibration and receptor degradation protects it from diffusion. The model predicts an optimal diffusion coefficient that maximizes receptor polarization, and shows that cells respond to relative - not absolute - changes in ligand levels. Cooperative receptor interactions further amplify the polarized response. Finally, stochastic analysis identifies an optimal set point that maximizes the signal-to-noise ratio in polarization. A survey of kinetic parameters across diverse receptor systems supports LAGS as a general mechanism for receptor-mediated directional sensing. Significance statementCells navigate their spatially heterogeneous environments by detecting spatial gradients of external signals - a process known as directional sensing. While traditionally attributed to downstream signaling pathways, we argue that cell surface receptors can themselves perform directional sensing by leveraging lateral diffusion, basal activity, and active receptor degradation. Using a reaction-diffusion model, we identify a general mechanism of directional sensing which we call Localized Activity and Global Sensitization (LAGS). In LAGS, degradation-driven integral feedback and receptor diffusion together generate robust, spatially polarized receptor activity. Our results suggest that directional sensing can emerge directly from receptor-level dynamics, revealing a broadly applicable strategy encoded in the biophysics of diverse signaling systems.