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

TL;DR

This paper develops a thermodynamics-based theoretical model to understand how GPCRs switch states, revealing multiple stable configurations influenced by chemical flux and phosphorylation, with implications for broader biological switches.

Contribution

The paper introduces a first principles nonequilibrium thermodynamics model for GPCR switching, highlighting the roles of chemical flux and phosphorylation in state stability and information transmission.

Findings

GPCRs can occupy three quasi-stable states with distinct information transmission capacities.

Active states involve chemical flux and on/off configurations, inactive states lack flux.

Phosphatase activity primarily controls switch occupancy, while kinase maintains flux.

Abstract

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 defin 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.