Spatiotemporal modeling of GPCR signaling: The role of endosomal dynamics and receptor recycling.

A growing number of G Protein-Coupled Receptors (GPCRs) have been reported to initiate signaling both at the cell surface and from intracellular compartments such as endosomes. The kinetics and spatial localization of these signals are critical determinants of cellular responses, yet receptor trafficking - including internalization, endosomal sorting, and recycling - remains a pivotal but often overlooked component of theoretical GPCR models. Here, we present a generic GPCR dynamic model that explicitly integrates receptor trafficking and signaling compartmentalization, enabling systematic characterization of the role of endosomal dynamics and receptor recycling on ligand-induced cellular responses. Then, as a case study, a model selection method with high-throughput kinetic data from the follicle-stimulating hormone receptor (FSHR) is used to reveal the impact of receptor trafficking on FSH-induced signaling responses. Although only a small fraction of FSHRs is internalized, these receptors produce a highly active endosomal response, underscoring the strong effect that any drug perturbing receptor trafficking can have. Our approach thus provides a refined tool for the pharmacological characterization of ligands and advances understanding of the spatial organization of FSHR signaling. Beyond this specific receptor, the methodology offers a generalizable strategy for modeling GPCR trafficking dynamics.