CXCR3

Chemokine receptor CXCR3 is a Gα_i protein-coupled receptor in the

Binding of CXCL9, CXCL10, and CXCL11 to CXCR3 is able to elicit increases in intracellular Ca²⁺⁺ levels and activate phosphoinositide 3-kinase and mitogen-activated protein kinase (MAPK).^[9] 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 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

CXCR3 has been implicated in the following diseases atherosclerosis,^[12] multiple sclerosis,^[13] pulmonary fibrosis,^[14] type 1 diabetes,^[15] autoimmune myasthenia gravis, nephrotoxic nephritis,^[16] acute cardiac allograft rejection,^[17] allergic contact dermatitis,^[18] and possibly Celiac Disease.^[19] It may also have implications in lung tissue repair after exposure to cigarette smoking.^[20] Development of agents to block CXCR3-ligand interactions may provide new ways to treat these diseases. In addition, CXCR3 has been implicated in inflammatory brain damage in central nervous system (CNS) infections^{[21][22][23][24][25][26]}

Cardiovascular implications

Evidence from pre-clinical and clinical investigations has revealed the involvement of CXCR3 and its ligands in several cardiovascular diseases (CVDs) of diverse etiologies including atherosclerosis, hypertension, Kawasaki disease, myocarditis, dilated cardiomyopathies, Chagas, cardiac hypertrophy and heart failure, as well as in heart transplant rejection and transplant coronary artery disease (CAD).^[5][27] CXCL9-10-11 have been recognized to be valid biomarkers for the development of heart failure and left ventricular dysfunction in two pilot studies, suggesting an underlining correlation between levels of the interferon (IFN)-γ-inducible chemokines and the development of adverse cardiac remodeling.^{[28] [29]}

Pharmacology

Recent reports indicate that there is a significant interest for the identification of small-molecule antagonists of CXCR3.^[30] Several small molecules ^[31] 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.^[32]

See also

• Chemokine receptors
• Chemokine
• Cluster of differentiation

References