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
chemokineCX3CL1 (also called neurotactin in mice or fractalkine in humans). This
endogenous ligand solely binds to CX3CR1 receptor. Interaction of CX3CR1 with CX3CL1 can mediate
migration,
adhesion and retention of leukocytes, because Fractalkine exists as membrane-anchored protein (mCX3CL1) as well as cleaved soluble molecule (sCX3CL1) due to
proteolysis by
metalloproteinases (MPPs). The shedded form carries out typical function of conventional chemokines, the
chemotaxis, while the membrane-bound protein behaves as
adhesion molecule for facilitation of
diapedesis.[7][8]
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]
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]
In the recognition of
immune cells during
inflammation, the function of CX3CL1-CX3CR1 axis in the
bloodstream is mainly recruitment of immune cells by migration through
chemotaxis and
diapedesis. Of course, as a part of the inflammatory
immune response against
pathogens this role considered as protective. However, as with most immune cells and proteins, in inflammatory or
autoimmune diseases, CX3CR1 signalling is associated with some disease's
pathophysiology.[7]
CX3CR1 is
integral membrane protein formed by 355
amino acids with molecular weight around 40 kDa, which consist of three distinguishable segments: extracellular, transmembrane and intracellular part.[7][8] As a member of the biggest class of
GPCR family the rhodopsin-like receptors, the intracellular part of receptor, C-terminus of the
polypeptide and three intracellular loops, is a bounding place with conserved DRYLAIV motif for the
heterotrimeric G protein. This family is also known as T-transmembrane receptors (7-TM) by reason of 7
α-helices of
transmembrane protein, which are alternately located in the cell's
cytoplasmic membrane.[12][16] Extracellular side of CX3CR1 consists of N-terminus of the polypeptide chain and three extracellular loops, forming a binding place for its main ligand
CX3CL1, but also
CCL26 (Eotaxin-3): has lower
binding affinity when compared to fractalkine), immunoglobulins or infectious agents.[9][10]
Signalling cascade
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
HIV-1 infection and rapid progression to
AIDS.[23]
Mutations in CX3CR1 are associated to
dysplasia of the hip.[26]
Homozygous CX3CR1-M280 mutation impairs human monocyte survival and deteriorates outcome of human systemic candiasis.[27]
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]
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