CX3C motif chemokine receptor 1

CX3C motif chemokine receptor 1 (CX3CR1), also known as the fractalkine receptor or G-protein coupled receptor 13 (GPR13), is a transmembrane protein of the G protein-coupled receptor 1 (GPCR1) family and the only known member of the CX3C chemokine receptor subfamily.^[5][6][7]

As the name suggests, this receptor binds the inflammatory

Both partners of CX3CL1-CX3CR1 axis are present on numerous cell types from hematopoietic and nonhematopoietic cells throughout the body. Moreover, their distinct cell expression is dependent on specific tissues and organs, which provides broad sphere of biological activity. Hence, considering their various functional activity, they are also linked with multiple neurodegenerative and inflammatory disorders as well as with tumorigenesis.^[7][8][9]

Genetics

The coding gene for CX3CR1 is now officially called identically to its protein: CX3CR1 gene,^[5][6] but may be still referred to by other older names such as V28; CCRL1; GPR13; CMKDR1; GPRV28; CMKBRL1. A genome location of the gene in humans is on the short arm of the chromosome 3p22.2. It is composed of four exons (only one contains coding region) and three intronic elements. Expression of the genomic sequence is regulated via three promoters.^[10][11]

Two missense mutations in CX3CR1 gene, variants of single nucleotide polymorphism (SNP) of the receptor, are responsible for functional change of the protein. Names of these variants are derived from given substitution and its position: valine to isoleucine (V249I) and threonine to methionine (T280M). Polymorphism of CX3CR1 has been linked to diseases relating to cardiovascular system (e.g. Atherosclerosis), nervous system (e.g. Alzheimer's disease, Sclerosis) or infections (e.g. systemic candidiasis.^[12][13][14]

Orthologs of CX3CR1 gene are found among animals, especially in mammals with high functional similarity, namely chimpanzee, dog, cat, mouse and rat. Orthologs are located on chromosome 9qF4 in the mouse genome and in the rat 8th chromosome on position 8q32.^[15][16]

Expression

CX3CR1 is expressed constitutively or in inflammatory response in various cells from hematopoietic lineage: T lymphocytes, natural killer (NK) cells, dendritic cells, B lymphocytes, mast cells, monocytes, macrophages, neutrophils, microglia, osteoclasts and thrombocytes. Furthermore, this receptor can be also found in nonhematopoietic tissues such as endothelial cells, epithelial cells, myocytes and astrocytes. Considering the CX3CR1 abundance in the body, it was also found to be expressed by some types of malignant cells.^{[9][10][12][17]}

Function

The CX3CR1 receptor is part of the G-protein chemokine receptor family with the metabotropic function. Its intracellular signalling cascades are responsible for modulating cell activity rather towards higher active state as in survival, migration and proliferation.^[7][18]

In the recognition of

The CX3CL1/CX3CR1 axis role in the nervous system is to mediate communication between microglia, neuroglia and neurons for regulation of microglia activity, hence this axis plays a neurodegenerative and neuroprotective function based on the physiological state.^[7][9]

Fractalkine signaling has also recently been discovered to play a developmental role in the migration of microglia in the central nervous system to their synaptic targets, where phagocytosis and synaptic refinement occur. CX3CR1 knockout mice had more synapses on hippocampal neurons than wild-type mice.^[21]

Structure

CX3CR1 is

CX3CL1-CX3CR1 axis' signalling commences via activation of the receptor by its agonist's binding. It is followed by conformational change and component's dissociation of the heterotrimeric G complex, which consists of three subunits: α (alpha), β (beta) and γ (gamma). Several important signalling pathways are triggered by separated parts of G protein (Gα and Gβγ) such as the PLC/PKC pathway, the PI3K/AKT/NFκB pathway, the Ras/Raf/MEK/ERK (MAPK) pathway (or p38 and JNK) and the CREB pathway. All of those signalling cascades are responsible for diverse cellular behaviours and regulations, in terms of increased proliferation, survival and cell growth, metabolic regulation, induction of migration, apoptosis resistance and secretion of hormones and inflammatory cytokines. Products of CX3CR1 signalling cascades possess importance in the immune response of CX3CR1 positive hematopoietic cells.^[9][10][18]

Clinical significance

CX3CR1 and immune cells are strongly connected due to its abundant cell surface expression. Therefore, clinical meaning of CX3CR1 can be found in diseases connected with immunity. CX3CR1 is able to increase accumulation of immune cells in the affected body part, which results in disease aggravation. Few examples: allergies, Rheumatoid arthritis, Renal diseases, Chronic liver disease or Crohn's disease.^[10][18][22]

CX3CR1 is also a coreceptor for HIV-1, and some variations in this gene lead to increased susceptibility to

Since CX3CR1 plays a major role for interaction between endothelial cells and immune cells, it can aid vascular build up on the artery walls (plaque), thus it has been associated with Atherosclerosis. In addition, this may lead to thrombosis, other cardiovascular diseases or even cerebral ischemia.^[10][18][17]

CX3CL1-CX3CR1 axis has an ability to control

As mentioned before, this receptor and its ligand are important for the metabolism of the bone tissue in terms of differentiation of osteoclasts and osteoblasts. Overactivation of osteoclasts as well as accumulation of other immune cells has been linked to Osteoporosis.^[9][17][8]

CX3CR1 with Fractalkine have a meaningful place also in many various types of cancer (e.g. Neuroblastoma, Prostate cancer, Gastric adenocarcinoma or B cell lymphomas) where CX3CL1-CX3CR1 axis is a double agent, providing antitumoral effects (stimulating and recruiting immune cells to target neoplasm) and protumoral effects (stimulating important activity in malignant cells like: invasion, proliferation and apoptosis resistance, for facilitating metastasis). Therefore, it has a lot of potential as therapeutical target in cancer.^[9][10][18]

References