Spatiotemporal Modeling of GPCR Signaling: The Role of Endosomal Dynamics and Receptor Recycling

Cells communicate through extracellular ligands such as hormones. Once recognized by their receptors at the plasma membrane, these ligands trigger intracellular signaling cascades. G Protein-Coupled Receptors (GPCRs) can initiate signaling both at the plasma membrane and, upon internalization, some are able to signal from intracellular compartments such as endosomes. Signal kinetics and spatial localization are major determinants of cellular responses to stimuli. Receptor trafficking (internalization, endosomal sorting, including recycling back to the plasma membrane) is therefore a key, yet often overlooked, component in theoretical GPCR models. Here, we have developed a mathematical framework integrating receptor trafficking and signal compartmentalization into generic GPCR dynamic models. Using a compartmentalized model based on systems of ordinary differential equations (Chemical Reaction Networks), we have analyzed the effects of receptor internalization and recycling on ligand-induced responses. Depending on the balance between plasma membrane and endosomal signaling, receptor trafficking can enhance or reduce ligand efficacy. Calibrated with high-throughput kinetic data, our model improves ligand pharmacological characterization and deepens understanding of compartmentalized GPCR signaling.