Differential receptor activation defines the fundamental limit of chemotactic sensing

1Cells are often assumed to require a [~]1% difference in ligand concentration across their length to bias chemotaxis, but this {Delta}C 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 ({Delta}{Omega}), 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 {Delta}C. 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%.