Modeling the role of homologous receptor desensitization in cell gradient sensing.
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.
Lin
Francis
F
Department of Pathology, Laboratory of Immunology and Vascular Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA. flin2@stanford.edu
Butcher
Eugene C
EC
D016175:B-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D054382:Chemokine CXCL13 / Q000096:biosynthesis / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D006801:Humans; D007424:Intracellular Fluid / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D018448:Models, Immunological; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D054400:Receptors, CCR7 / Q000096:biosynthesis / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D040681:Structural Homology, Protein; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
C515370:CCR7 protein, human; C110663:CXCL13 protein, human; C095085:CXCR5 protein, human; D054382:Chemokine CXCL13; D008024:Ligands; D054400:Receptors, CCR7; D054380:Receptors, CXCR5