Information Transmission and Processing in G-Protein-Coupled-Receptor Complexes.

G-protein-coupled receptors (GPCRs) are central to cellular information processing, yet the physical principles governing their switching behavior remain incompletely understood. We present a first-principles theoretical framework, grounded in nonequilibrium thermodynamics, to describe GPCR switching as observed in light-controlled impedance assays. The model identifies two fundamental control parameters: (1) ATP/GTP-driven chemical flux through the receptor complex, and (2) the free-energy difference between phosphorylated and dephosphorylated switch states. Together, these parameters define the switch configuration. The model predicts that GPCRs can occupy one of three quasi-stable configurations, each corresponding to a local maximum in information transmission. Active states support chemical flux and exist in an "on" or "off" switch configuration, whereas inactive states lack flux, introducing a distinction absent in conventional phosphorylation models. The model takes two ligand-derived inputs: fixed structural features and inducible conformations (e.g. cis or trans). It shows that phosphatase activity, modeled as an energy barrier, chiefly governs "on"/"off" occupancy, whereas the kinase sustains flux without directly determining the switch configuration. Comparison with experimental data confirms the predicted existence of multiple quasi-stable states modulated by ligand conformation. Importantly, this framework generalizes beyond GPCRs to encompass a wider class of biological switching systems driven by nonequilibrium chemical flux.