title: CXC Chemokine Receptor 3 Alternative Splice Variants Selectively Activate Different Signaling Pathways.
abstract: The G protein-coupled receptor (GPCR) C-X-C chemokine receptor 3 (CXCR3) is a potential drug target that mediates signaling involved in cancer metastasis and inflammatory diseases. The CXCR3 primary transcript has three potential alternative splice variants and cell-type specific expression results in receptor variants that are believed to have different functional characteristics. However, the molecular pharmacology of ligand binding to CXCR3 alternative splice variants and their downstream signaling pathways remain poorly explored. To better understand the role of the functional consequences of alternative splicing of CXCR3, we measured signaling in response to four different chemokine ligands (CXCL4, CXCL9, CXCL10, and CXCL11) with agonist activity at CXCR3. Both CXCL10 and CXCL11 activated splice variant CXCR3A. Whereas CXCL10 displayed full agonistic activity for Gαi activation and extracellular signal regulated kinase (ERK) 1/2 phosphorylation and partial agonist activity for β-arrestin recruitment, CXCL9 triggered only modest ERK1/2 phosphorylation. CXCL11 induced CXCR3B-mediated β-arrestin recruitment and little ERK phosphorylation. CXCR3Alt signaling was limited to modest ligand-induced receptor internalization and ERK1/2 phosphorylation in response to chemokines CXCL11, CXCL10, and CXCL9. These results show that CXCR3 splice variants activate different signaling pathways and that CXCR3 variant function is not redundant, suggesting a mechanism for tissue specific biased agonism. Our data show an additional layer of complexity for chemokine receptor signaling that might be exploited to target specific CXCR3 splice variants.
authors: Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York (Y.A.B.; T.P.S.); and Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden (T.P.S).
authors: Yamina A
authors: YA
authors: Berchiche
authors: Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York (Y.A.B.; T.P.S.); and Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden (T.P.S) sakmar@rockefeller.edu.
authors: Thomas P
authors: TP
authors: Sakmar
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D018925:Chemokines / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D054367:Receptors, CXCR3 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D000071557:beta-Arrestins / Q000378:metabolism
chemical_list: D018925:Chemokines; D054367:Receptors, CXCR3; D000071557:beta-Arrestins; D037342:Pertussis Toxin; D048049:Extracellular Signal-Regulated MAP Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go