title: Intracellular domains of CXCR3 that mediate CXCL9, CXCL10, and CXCL11 function.
abstract: The chemokine receptor CXCR3 is a G protein-coupled receptor found predominantly on T cells that is activated by three ligands as follows: CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (I-TAC). Previously, we have found that of the three ligands, CXCL11 is the most potent inducer of CXCR3 internalization and is the physiologic inducer of CXCR3 internalization after T cell contact with activated endothelial cells. We have therefore hypothesized that these three ligands transduce different signals to CXCR3. In light of this hypothesis, we sought to determine whether regions of CXCR3 are differentially required for CXCL9, CXCL10, and CXCL11 function. Here we identified two distinct domains that contributed to CXCR3 internalization. The carboxyl-terminal domain and beta-arrestin1 were predominantly required by CXCL9 and CXCL10, and the third intracellular loop was predominantly required by CXCL11. Chemotaxis and calcium mobilization induced by all three CXCR3 ligands were dependent on the CXCR3 carboxyl terminus and the DRY sequence in the third trans-membrane domain. Our findings demonstrate that distinct domains of CXCR3 mediate its functions and suggest that the differential requirement of these domains contributes to the complexity of the chemokine system.
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Colvin
authors.forename: Gabriele S V
authors.initials: GS
authors.lastname: Campanella
authors.forename: Jieti
authors.initials: J
authors.lastname: Sun
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
mesh_terms: D000595:Amino Acid Sequence; D019390:Arrestins / Q000378:metabolism; D001665:Binding Sites; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000737:chemistry*; D002633:Chemotaxis; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D034281:Dynamins / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry*; D008024:Ligands; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000737:chemistry*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D018076:DNA, Complementary; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D000071557:beta-Arrestins; D034281:Dynamins; D002118:Calcium