CXCR3

Chemokine receptor CXCR3 is a Gαi protein-coupled receptor in the CXC chemokine receptor family. Other names for CXCR3 are G protein-coupled receptor 9 (GPR9) and CD183. There are two variants of CXCR3: CXCR3-A binds to the CXC chemokines is_associated_with::CXCL9 (MIG), is_associated_with::CXCL10 (IP-10), and is_associated_with::CXCL11 (I-TAC) whereas CXCR3-B can also bind to is_associated_with::CXCL4 in addition to CXCL9, CXCL10, and CXCL11.

Expression
CXCR3 is expressed primarily on activated is_associated_with::T lymphocytes and is_associated_with::NK cells, and some epithelial cells. CXCR3 and is_associated_with::CCR5 are preferentially expressed on is_associated_with::Th1 cells, whereas Th2 cells favor the expression of CCR3 and is_associated_with::CCR4. CXCR3 ligands that attract Th1 cells can concomitantly block the migration of Th2 cells in response to CCR3 ligands, thus enhancing the polarization of effector T cell recruitment.

Signal transduction
Binding of CXCL9, CXCL10, and CXCL11 to CXCR3 is able to elicit increases in intracellular Ca2++ levels and activate is_associated_with::phosphoinositide 3-kinase and is_associated_with::mitogen-activated protein kinase (MAPK). Detailed signaling pathway has not yet been established, but may include the same enzymes that were identified in the signaling cascade induced by other chemokine receptors.

Function
CXCR3 is able to regulate leukocyte trafficking. Binding of chemokines to CXCR3 induces various cellular responses, most notably is_associated_with::integrin activation, cytoskeletal changes and chemotactic migration. CXCR3-ligand interaction attracts Th1 cells and promotes Th1 cell maturation.

As a consequence of chemokine-induced cellular desensitization (phosphorylation-dependent receptor internalization), cellular responses are typically rapid and short in duration. Cellular responsiveness is restored after is_associated_with::dephosphorylation of intracellular receptors and subsequent recycling to the cell surface. A hallmark of CXCR3 is its prominent expression in in vitro cultured effector/memory T cells, and in T cells present in many types of inflamed tissues. In addition, CXCL9, CXCL10 and CXCL11 are commonly produced by local cells in inflammatory lesion, suggesting that CXCR3 and its chemokines participate in the recruitment of inflammatory cells. Additionally, CXCR3 has been implicated in wound healing.

Clinical significance
CXCR3 has been implicated in the following diseases, is_associated_with::atherosclerosis, is_associated_with::multiple sclerosis, is_associated_with::pulmonary fibrosis, is_associated_with::type 1 diabetes, autoimmune myasthenia gravis, is_associated_with::nephrotoxic nephritis, acute cardiac allograft rejection and possibly Celiac Disease. Development of agents to block CXCR3-ligand interactions may provide new ways to treat these diseases.

Pharmacology
Recent reports indicate that there is a significant interest for the identification of small-molecule antagonists of CXCR3. Several small molecules were found to constitute a promising series of functional antagonists of CXCR3 that could be developed into new therapeutic agents for the treatment of inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease,multiple sclerosis and diabetes. More recently the first QSAR study concerning antagonists of CXCR3 has been published in the literature. The in silico model provides a time- and cost-effective tool for the screening of existing and virtual libraries of small molecules as well as for designing of novel molecules of desired activity.

Interactions
CXCR3 has been shown to interact with is_associated_with::CXCL9.