Ratiometric signaling produces robust temporal integration for accurate cellular gradient sensing

Abstract

Cells excel at interpreting noisy chemical gradients to guide fertilization, development, and immune responses, but the mechanisms underlying this remarkable ability remain poorly understood. Previous work showed that some G protein signaling pathways can overcome challenges from uneven receptor distribution by using a ratiometric signaling strategy. In this mechanism, G proteins receive information from both bound and unbound receptors, unlike classical signaling where only bound receptors contribute. Here, we show that ratiometric signaling also provides an unexpected ability to suppress noise from low receptor numbers. The benefit stems from each G protein remembering the last receptor state it encountered, so that at any instant, ratiometric G protein collectives reflect time-averaged receptor activity. Unlike classical signaling, this averaging remains unbiased and accurate across the varying ligand concentrations present in a spatial gradient. Using theory and simulations, we demonstrate that this averaging mechanism allows cells to surpass theoretical limits for gradient detection from instantaneous receptor information alone. Our findings reveal how ratiometric biochemical architectures enable robust temporal integration across spatially varying signals, providing cells with enhanced directional accuracy under noisy conditions.