Journal
JOURNAL OF IMMUNOLOGY
Volume 181, Issue 12, Pages 8335-8343Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.181.12.8335
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Funding
- National Institutes of Health-National Institute of Allergy and Infectious Diseases, Immunology program, Stanford University [5T32AI07290-20]
- Stanford Bio-X Interdisciplinary Initiative Program
- National Institutes of Health
- Department of Veterans Affairs
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G-protein-coupled chemoattractant receptors signal transiently upon ligand binding to effect cell orientation and motility but then are rapidly desensitized. The importance of desensitization has been unclear, because mutated nondesensitizable receptors mediate efficient chemotaxis. We hypothesized that homologous receptor desensitization is required for cellular navigation ill fields of competing attractants. Modeling of receptor-mediated orientation shows that desensitization allows integration of attractant signals. Cells expressing normal receptors are predicted to 1) orient preferentially to distant gradients; 2) seek an intermediate position between balanced agonist sources; 3) and call be repositioned between chemoattractant-defined microenvironmental domains by modest changes in receptor number. In contrast, in the absence of desensitization, orientation is dominated by local agonist sources, precluding continued navigation. Furthermore, cell orientation in competing ligand gradients depends on the relative kinetic rates of receptor desensitization and recycling. We propose that homologous receptor desensitization is critical for cellular navigation in complex chemoattractant fields. The Journal of Immunology, 2008, 181: 8335-8343.
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