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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.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1014790","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:35:56Z","timestamp":1790703356000},"page":"e1014790","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatiotemporal modeling of GPCR signaling: The role of endosomal dynamics and receptor recycling"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8868-7530","authenticated-orcid":true,"given":"Chlo\u00e9","family":"Weckel","sequence":"first","affiliation":[{"name":"Musca, Inria, Universit\u00e9 Paris-Saclay, Inria Saclay-Ile-de-France","place":["Palaiseau, France"]},{"name":"PRC, INRAE, CNRS, Universit\u00e9 de Tours","place":["Nouzilly, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0746-6618","authenticated-orcid":true,"given":"Juliette","family":"Gourdon","sequence":"additional","affiliation":[{"name":"PRC, INRAE, CNRS, Universit\u00e9 de Tours","place":["Nouzilly, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9o","family":"Darrigade","sequence":"additional","affiliation":[{"name":"Musca, Inria, Universit\u00e9 Paris-Saclay, Inria Saclay-Ile-de-France","place":["Palaiseau, France"]},{"name":"PRC, INRAE, CNRS, Universit\u00e9 de Tours","place":["Nouzilly, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinesh","family":"Jugnarain","sequence":"additional","affiliation":[{"name":"PRC, INRAE, CNRS, Universit\u00e9 de Tours","place":["Nouzilly, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Cr\u00e9pieux","sequence":"additional","affiliation":[{"name":"Musca, Inria, Universit\u00e9 Paris-Saclay, Inria Saclay-Ile-de-France","place":["Palaiseau, France"]},{"name":"PRC, INRAE, CNRS, Universit\u00e9 de Tours","place":["Nouzilly, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Reiter","sequence":"additional","affiliation":[{"name":"Musca, Inria, Universit\u00e9 Paris-Saclay, Inria Saclay-Ile-de-France","place":["Palaiseau, France"]},{"name":"PRC, INRAE, CNRS, Universit\u00e9 de Tours","place":["Nouzilly, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Jean-Alphonse","sequence":"additional","affiliation":[{"name":"Musca, Inria, Universit\u00e9 Paris-Saclay, Inria Saclay-Ile-de-France","place":["Palaiseau, France"]},{"name":"PRC, INRAE, CNRS, Universit\u00e9 de Tours","place":["Nouzilly, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Haar","sequence":"additional","affiliation":[{"name":"Musca, Inria, 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