Spatiotemporal modeling of GPCR signaling: The role of endosomal dynamics and receptor recycling
- 1Musca, Inria, Université Paris-Saclay, Inria Saclay-Ile-de-France, Palaiseau, France
- 2PRC, INRAE, CNRS, Université de Tours, Nouzilly, France
Abstract
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. Author summary: Cell signaling pathways have long been viewed as being activated by interactions between extracellular ligands and a relatively static pools of membrane receptors. However, growing evidence shows that ligand–receptor interactions trigger complex spatial trafficking processes and activate signaling pathways at distinct intracellular locations (e.g., endosomes). This has led to the emergence of a new paradigm of compartmentalized signaling, which remains poorly understood but offers exciting pharmacological opportunities. In this study, we adapt a well-established ordinary differential equation framework to describe cell signaling pathways by explicitly incorporating receptor trafficking and compartmentalized signaling. Our steady-state analysis demonstrates the critical role of both receptor trafficking and compartmentalized signaling in shaping cellular responses, providing further evidence that these mechanisms should be considered in drug design. We then apply a quantitative model selection and calibration approach on the follicle-stimulating hormone receptor (FSHR) using kinetic data on receptor trafficking and signaling dynamics. The FSHR has been characterized to internalize in distinct and peculiar endosomal compartments, whose dynamics remain unclear. Our results reveal dynamic spatial trafficking in three distinct compartments, that strongly influences signaling outcomes. This quantitative framework provides new insights into follicle-stimulating hormone receptor pharmacology, with broader implications for reproductive management in both human health and livestock production.
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BibTeX
@article{weckel2026spatiotemporal,
title = {{Spatiotemporal modeling of GPCR signaling: The role of endosomal dynamics and receptor recycling}},
author = {Chloé Weckel and Juliette Gourdon and Léo Darrigade and Vinesh Jugnarain and Pascale Crépieux and Eric Reiter and Frédéric Jean-Alphonse and Stefan Haar and Romain Yvinec},
journal = {PLOS Computational Biology},
year = {2026},
month = sep,
doi = {10.1371/journal.pcbi.1014790},
url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014790},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Spatiotemporal modeling of GPCR signaling: The role of endosomal dynamics and receptor recycling
AU - Chloé Weckel
AU - Juliette Gourdon
AU - Léo Darrigade
AU - Vinesh Jugnarain
AU - Pascale Crépieux
AU - Eric Reiter
AU - Frédéric Jean-Alphonse
AU - Stefan Haar
AU - Romain Yvinec
PY - 2026
DA - 2026/09/29
JO - PLOS Computational Biology
DO - 10.1371/journal.pcbi.1014790
UR - https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014790
AB - 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. Author summary: Cell signaling pathways have long been viewed as being activated by interactions between extracellular ligands and a relatively static pools of membrane receptors. However, growing evidence shows that ligand–receptor interactions trigger complex spatial trafficking processes and activate signaling pathways at distinct intracellular locations (e.g., endosomes). This has led to the emergence of a new paradigm of compartmentalized signaling, which remains poorly understood but offers exciting pharmacological opportunities. In this study, we adapt a well-established ordinary differential equation framework to describe cell signaling pathways by explicitly incorporating receptor trafficking and compartmentalized signaling. Our steady-state analysis demonstrates the critical role of both receptor trafficking and compartmentalized signaling in shaping cellular responses, providing further evidence that these mechanisms should be considered in drug design. We then apply a quantitative model selection and calibration approach on the follicle-stimulating hormone receptor (FSHR) using kinetic data on receptor trafficking and signaling dynamics. The FSHR has been characterized to internalize in distinct and peculiar endosomal compartments, whose dynamics remain unclear. Our results reveal dynamic spatial trafficking in three distinct compartments, that strongly influences signaling outcomes. This quantitative framework provides new insights into follicle-stimulating hormone receptor pharmacology, with broader implications for reproductive management in both human health and livestock production.
SN - 1553-7358
ER -