Directional Sensing by Eukaryotic Receptors

Directional sensing enables eukaryotic cells to detect spatial gradients of extracellular ligands. Prevailing theoretical models of directional sensing invoke the Local Excitation Global Inhibition (LEGI) architecture, in which two signaling species with vastly different diffusion constants act incoherently on a downstream readout. Here we introduce a fundamentally different mechanism in which directional sensing arises at the receptor level without requiring diffusion differentials and incoherent action. Our model integrates three ubiquitous receptor processes ---lateral diffusion, basal ligand-independent receptor activation, and active receptor degradation. Each process is individually detrimental to asymmetric receptor activity, yet together they synergize to generate robust directional sensing. In the absence of diffusion, active receptor degradation implements an integral feedback that adapts active receptor levels to a ligand-independent set point while depleting total receptor levels in ligand-rich regions. Diffusion then redistributes receptors across the surface, creating a spatial mismatch between activity and feedback that drives directionally asymmetric receptor activity relative to the set point. The model predicts an optimal diffusion constant that maximizes active receptor polarization, demonstrates that  receptors can encode relative rather than absolute ligand concentrations, and reveals optimal basal activity that maximizes the signal-to-noise ratio in stochastic regimes. A survey of kinetic parameters across receptor families supports this diffusion–degradation synergy as a general, receptor-level mechanism for directional sensing.