CX3C motif chemokine receptor 1 (CX3CR1), also known as the fractalkine receptor or G-protein coupled receptor 13 (GPR13), is a

transmembrane protein A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequent ...

of the

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

1 (GPCR1) family and the only known member of the CX3C chemokine receptor subfamily. As the name suggests, this receptor binds the inflammatory

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...

CX3CL1 Fractalkine, also known as chemokine (C-X3-C motif) ligand 1, is a protein that in humans is encoded by the CX3CL1 gene. Function Fractalkine is a large cytokine protein of 373 amino acids, it contains multiple domains and is the only known me ...

(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 Migration, migratory, or migrate may refer to: Human migration * Human migration, physical movement by humans from one region to another ** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...

adhesion Adhesion is the tendency of dissimilar particles or surfaces to cling to one another ( cohesion refers to the tendency of similar or identical particles/surfaces to cling to one another). The forces that cause adhesion and cohesion can b ...

and retention of leukocytes, because Fractalkine exists as membrane-anchored protein (mCX3CL1) as well as cleaved soluble molecule (sCX3CL1) due to proteolysis by

metalloproteinases A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myoge ...

(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 Leukocyte extravasation (also commonly known as leukocyte adhesion cascade or diapedesis – the passage of cells through the intact vessel wall) is the movement of leukocytes out of the circulatory system and towards the site of tissue damage o ...

. 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 A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

and inflammatory disorders as well as with

tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...

Genetics

The coding

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

for CX3CR1 is now officially called identically to its

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

: ''CX3CR1 gene'', but may be still referred to by other older names such ''as V28; CCRL1; GPR13; CMKDR1; GPRV28; CMKBRL1''. A

genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...

location of the gene in humans is on the short arm of the

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

3p22.2. It is composed of four exons (only one contains coding region) and three

intronic An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene ...

elements. Expression of the genomic sequence is regulated via three promoters. Two

missense mutations In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

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 Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...

to isoleucine (V249I) and threonine to methionine (T280M). Polymorphism of CX3CR1 has been linked to diseases relating to cardiovascular system (e.g.

Atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...

nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...

(e.g. Alzheimer's disease, Sclerosis) or

infections An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...

(e.g. systemic candidiasis.

Orthologs Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...

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 8^th chromosome on position 8q32.

Expression

CX3CR1 is expressed constitutively or in inflammatory response in various cells from hematopoietic lineage:

T lymphocytes A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...

, natural killer (NK) cells,

dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...

B lymphocytes B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

mast cells A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a ...

, monocytes,

macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

, neutrophils, microglia,

osteoclasts An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated prote ...

and

thrombocytes Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby in ...

. Furthermore, this receptor can be also found in nonhematopoietic tissues such as

endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

epithelial cells Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...

myocytes A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscl ...

and

astrocytes Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...

. Considering the CX3CR1 abundance in the body, it was also found to be expressed by some types of malignant cells.

Function

CX3CR1 receptor is part of

G-protein G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...

chemokine receptor family with the

metabotropic A metabotropic receptor, also referred to by the broader term G-protein-coupled receptor, is a type of membrane receptor that initiates a number of metabolic steps to modulate cell activity. The nervous system utilizes two types of receptors: met ...

function. Its intracellular signalling cascades are responsible for modulating cell activity rather towards higher active state as in survival,

and proliferation. In the recognition for

immune cells White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

during

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

, function of CX3CL1-CX3CR1 axis in the

bloodstream The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

is mainly recruitment of immune cells by migration through chemotaxis and

. Of course as a part of inflammatory

immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...

against

pathogens In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a ger ...

is this role considerated as protective. However, as most of immune cells and proteins, in inflammatory or

autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...

diseases, CX3CR1 signalling is associated with some disease's pathophysiology. Expression of this receptor appears to be associated with lymphocytes. CX3CR1 is also expressed by monocytes and plays a major role in the survival of monocytes. Communication in blood vessels through CX3CL1-CX3CR1 axis between

and monocytes is responsible for formation of

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...

and angiogenesis. It was shown, that CX3CR1 can influence monocytes already in bone marrow by means of retention and release. Moreover in bone marrow, CX3CR1 influences

bone remodeling Bone remodeling (or bone metabolism) is a lifelong process where mature bone tissue is removed from the skeleton (a process called ''bone resorption'') and new bone tissue is formed (a process called ''ossification'' or ''new bone formation''). ...

through role in differentiation of

and

osteoblasts Osteoblasts (from the Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts function ...

. CX3CL1/CX3CR1 axis role in neurvous system is to mediate communication between microglia, neuroglia and neurons for regulation of microglia activity, hence this axis plays

and

neuroprotective Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...

function based on the physiological state. Fractalkine signaling has also recently been discovered to play a developmental role in the migration of microglia in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

to their synaptic targets, where

phagocytosis Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...

and synaptic refinement occur. CX3CR1 knockout mice had more synapses on

hippocampal The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, an ...

neurons than wild-type mice.

Structure

CX3CR1 is

integral membrane protein An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a sign ...

formed by 355 amino acids with molecular weight around 40 kDa, which consist of three distinguishable segments: extracellular, transmembrane and intracellular part. 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 Heterotrimeric G protein, also sometimes referred to as the ''"large" G proteins'' (as opposed to the subclass of smaller, monomeric small GTPases) are membrane-associated G proteins that form a heterotrimeric complex. The biggest non-structu ...

. This family is also known as T-transmembrane receptors (7-TM) by reason of 7

α-helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

, which are alternately located in the cell's

cytoplasmic membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (th ...

. Extracellular side of CX3CR1 consists of N-terminus of the polypeptide chain and three extracellular loops, forming a binding place for its main ligand

, but also CCL26 (Eotaxin-3): has lower

binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a m ...

when compared to fractalkine), immunoglobulins or infectious agents.

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 Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

AKT Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...

/ NFκB pathway, the Ras/Raf/MEK/ERK (

MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...

) pathway (or p38 and

JNK c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and ar ...

) and the

CREB CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first de ...

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 Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

, induction of

, apoptosis resistance and secretion of hormones and inflammatory cytokines. Products of CX3CR1 signalling cascades possess importance in the

of CX3CR1 positive hematopoietic cells.

Clinical significance

CX3CR1 and

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 Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermat ...

Rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

, Renal diseases,

Chronic liver disease Chronic liver disease in the clinical context is a disease process of the liver that involves a process of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis. "Chronic liver disease" refers to disease ...

or Crohn's disease. CX3CR1 is also a coreceptor for HIV-1, and some variations in this gene lead to increased susceptibility to

HIV-1 The subtypes of HIV include two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to viruses found in the sooty mangabey ...

infection and rapid progression to AIDS. Since CX3CR1 plays a major role for interaction between

and

, it can aid vascular build up on the

artery An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...

walls (plaque), thus it has been associated with

. In addition, this may lead to

thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (t ...

, other

cardiovascular diseases Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, ...

or even

cerebral ischemia Brain ischemia is a condition in which there is insufficient bloodflow to the brain to meet metabolic demand. This leads to poor oxygen supply or cerebral hypoxia and thus leads to the death of brain tissue or cerebral infarction/ischemic stroke. ...

. CX3CL1-CX3CR1 axis has an ability to control neurological inflammation through activation of microglia. Its role in brain pathologies can be therefore protective but also detrimental. There are connections between microglia and neurodegenerative disorders like Alzheimer's disease,

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

or even with neurocognitive

HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

dementia Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...

. Moreover, CX3CR1 variants have been described to modify the survival time and the progression rate of patients with amyotrophic lateral sclerosis. Mutations in CX3CR1 are associated to dysplasia of the hip. Homozygous CX3CR1-M280 mutation impairs human monocyte survival and deteriorates outcome of human systemic candiasis. As mentioned before, this receptor and its ligand are important for the

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...

of the

bone tissue A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, a ...

in terms of differentiation of

and

. Overactivation of osteoclasts as well as accumulation of other immune cells has been linked to Osteoporosis. CX3CR1 with Fractalkine have a meaningful place also in many various types of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

(e.g.

Neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in th ...

, Prostate cancer,

Gastric adenocarcinoma Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lym ...

or B cell lymphomas) where CX3CL1-CX3CR1 axis is a

double agent In the field of counterintelligence, a double agent is an employee of a secret intelligence service for one country, whose primary purpose is to spy on a target organization of another country, but who is now spying on their own country's organ ...

, providing antitumoral effects (stimulating and recruiting immune cells to target

neoplasm A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

) and protumoral effects (stimulating important activity in malignant cells like: invasion, proliferation and apoptosis resistance, for facilitating

metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then ...

). Therefore, it has a lot of potential as therapeutical target in

References

External links

* * * {{Chemokine receptor modulators Cytokines Cell biology Receptors Integral membrane proteins