Differential receptor activation defines the fundamental limit of chemotactic sensing

1 Abstract Cells are often assumed to require a ∼1% difference in ligand concentration across their length to bias chemotaxis, but this ΔC framework overlooks the non-linear relation between ligand concen-tration and receptor activation and, for linear gradients, is uninformative with respect to gradient steepness. Using mathematical modelling and experiments in linear gradients of the non-degradable cAMP analogue Sp-cAMPS, we show that ligand concentration alone does not describe chemotactic behaviour. By expressing signals as the differential proportion of activated receptors (ΔΩ), we find that cells can detect differences as small as 0.026% across their length. Importantly, the minimum differential required to induce bias increases with overall receptor activation, demonstrating that chemotactic sensitivity depends on the receptor occupancy regime rather than on ΔC. The true minimal chemotactic threshold therefore lies at concentrations that minimise receptor activation while still eliciting a bias, and is likely to be below 0.026%. Competing Interest Statement The authors have declared no competing interest.