Chemokines are small molecular weight, soluble secreted proteins that bind and activate their respective G-protein coupled receptor (GPCR), chemokine receptors in order to evoke a cellular response resulting in migration or chemotaxis¹.

The chemokine system involves more than 40 chemokines and 18 chemokine receptors. The receptors are designated CXCR1-5, CCR1-11, XCR1 and CX3CR1, based on their specific ligand preference².

Chemokine receptors are present on many different cell types. They were initially detected on leukocytes, where they were found to play an important role in the migration of these cells to inflammation sites³.

CXCR4 was originally identified as an orphan receptor, and soon gained much attention when it was discovered as a coreceptor for HIV-1⁴. Besides from being involved in HIV-1 infection/progression, CXCR4 is found to be upregulated in many different cancers/tumors and has evolved to become a target for the development of antagonists⁵. CXCL12 (SDF-1α) is the sole ligand for CXCR4. Following binding of its ligand, CXCR4 undergoes dimerization and activates G_i G-proteins^6,7. However downstream activation through CXCR4 could also occur through other G-proteins and non-G-proteins⁵. The down regulation of the CXCR4 receptor is initiated by phosphorylation of its cytoplasmic tail, which is followed by the binding of arrestin. The receptor is then internalized through endocytosis and degraded in the lysosome. Downregulation of CXCR4 could also occur through the stimulation of other GPCRs⁸.

The distribution of CXCR4 is quite broad and involves the central nervous system (CNS)⁹, spleen¹⁰, testes¹¹, hematopoietic and non-hematopoietic cells¹².