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Modeling the Role of Homologous Receptor Desensitization in Cell Gradient Sensing¹

Laboratory of Immunology and Vascular Biology, Department of Pathology, School of Medicine, Stanford University, Stanford, CA 94305; and Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304

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 in 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 can 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ F.L. is supported by the postdoctoral training grant (5T32AI07290-20) from the National Institutes of Health-National Institute of Allergy and Infectious Diseases, Immunology Program, Stanford University, and a grant from the Stanford Bio-X Interdisciplinary Initiative Program. This study is supported in part by grants from the National Institutes of Health and an award from the Department of Veterans Affairs to E.C.B.

² Address correspondence and reprint requests to Dr. Francis Lin, Laboratory of Immunology and Vascular Biology, Department of Pathology, School of Medicine, Stanford University, Stanford, CA 94305. E-mail address: flin2{at}stanford.edu or Dr. Eugene C. Butcher, Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Building 100, Room B4-145, Palo Alto, CA 94304. E-mail address: ebutcher{at}stanford.edu

³ Abbreviations used in this paper: LTB₄, leukotriene B₄; B/T junction, the junctional region between the B cell zone and T cell zone; 1-D, one-dimensional.

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