Receptor polarization through localized activity and global sensitization: A new principle for eukaryotic chemosensing

Eukaryotic cells can chemosense spatial concentration gradients of extracellular ligands using membrane-bound receptors that activate and create a polarized response. Notably, receptors from several chemosensing families are preferentially degraded after activation and undergo significant lateral diffusion, both of which may blunt their polarization. To explore the combined role of degradation and diffusion on receptor polarization, we use a simple reaction/diffusion model of a receptor-based signaling network. Our model elucidates a new chemosensing principle: polarization through Localized Activity and Global Sensitization (LAGS). In LAGS, rapid removal of receptor activity through preferential degradation or ligand unbinding keeps activity localized. At the same time, lateral diffusion spreads receptors along the cell membrane, supplementing regions which have reduced receptor levels due to preferential degradation, thereby maintaining an approximately uniform sensitivity for ligands. Counterintuitively, increasing preferential degradation of active receptors and increasing lateral diffusion of all receptors both sharpen receptor polarization. Additionally, when combined with receptor oligomerization, preferential receptor degradation allows cells to sense relative ligand gradients over a larger range of background ligand concentrations. For kinetic parameters typical to many receptor families, polarization is likely to be dictated by LAGS rather than differences in receptor diffusion rates, suggesting that many mammalian chemosensing pathways utilize the LAGS principle.