Adhesion G Protein-coupled Receptor
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Adhesion
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 ...
s (adhesion GPCRs) are a class of 33 human protein
receptors Receptor may refer to: *Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds ...
with a broad distribution in embryonic and larval cells, cells of the reproductive tract, neurons, leukocytes, and a variety of tumours. Adhesion GPCRs are found throughout
metazoans Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia (). With few exceptions, animals consume organic material, breathe oxygen, have myocytes and are able to move, can reproduce sexually, and grow from a ho ...
and are also found in single-celled colony forming
choanoflagellates Choanoflagellates are a group of free-living unicellular and colonial flagellate eukaryotes considered to be the closest living relatives of animals. The name refers to the characteristic funnel-shaped "collar" of interconnected microvilli and t ...
such as ''Monosiga brevicollis'' and unicellular organisms such as
Filasterea Filasterea is a proposed basal Filozoan clade of single-celled ameboid eukaryotes that includes '' Ministeria'' and '' Capsaspora''. It is a sister clade to the Choanozoa in which the Choanoflagellatea and Animals appeared, originally proposed b ...
. The defining feature of adhesion GPCRs that distinguishes them from other GPCRs is their hybrid molecular structure. The extracellular region of adhesion GPCRs can be exceptionally long and contain a variety of structural domains that are known for the ability to facilitate cell and matrix interactions. Their extracellular region contains the membrane proximal
GAIN Gain or GAIN may refer to: Science and technology * Gain (electronics), an electronics and signal processing term * Antenna gain * Gain (laser), the amplification involved in laser emission * Gain (projection screens) * Information gain in de ...
(GPCR-Autoproteolsis INducing) domain. Crystallographic and experimental data has shown this structurally conserved domain to mediate autocatalytic processing at a GPCR-proteolytic site (GPS) proximal to the first transmembrane helix. Autocatalytic processing gives rise to an extracellular (α) and a membrane-spanning (β) subunit, which are associated non-covalently, resulting in expression of a heterodimeric receptor at the cell surface. Ligand profiles and ''in vitro'' studies have indicated a role for adhesion GPCRs in cell adhesion and migration. Work utilizing genetic models confined this concept by demonstrating that the primary function of adhesion GPCRs may relate to the proper positioning of cells in a variety of organ systems. Moreover, growing evidence implies a role of adhesion GPCRs in tumour cell metastasis. Formal G protein-coupled signalling has been demonstrated for a number for adhesion GPCRs, however, the
orphan receptor In biochemistry, an orphan receptor is a protein that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred ...
status of many of the receptors still hampers full characterisation of potential signal transduction pathways. In 2011, th
adhesion GPCR consortium
was established to facilitate research of the physiological and pathological functions of adhesion GPCRs.


Classification

The GPCR superfamily is the largest gene family in the human genome containing approximately 800 genes. As the vertebrate superfamily can be phylogenetically grouped into five main families, the
GRAFS The GPCR superfamily is the largest gene family in the human genome containing approximately 800 genes. As the vertebrate superfamily can be phylogenetically grouped into five main families the GRAFS classification system has been proposed. GRAFS ...
classification system has been proposed, which includes the
glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
,
rhodopsin Rhodopsin, also known as visual purple, is a protein encoded by the ''RHO'' gene and a G-protein-coupled receptor (GPCR). It is a light-sensitive receptor protein that triggers visual phototransduction in rod cells. Rhodopsin mediates dim ...
, adhesion,
Frizzled Frizzled is a family of atypical G protein-coupled receptor, G protein-coupled receptors that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol ...
/ Taste2, and
secretin Secretin is a hormone that regulates water homeostasis throughout the body and influences the environment of the duodenum by regulating secretions in the stomach, pancreas, and liver. It is a peptide hormone produced in the S cells of the duodenum ...
GPCR families. There are 33 human adhesion GPCRs that can be broken down into eight groups, with two independent receptors. Group I consists of
LPHN1 Latrophilin 1 is a protein that in humans is encoded by the ''ADGRL1'' gene. It is a member of the adhesion-GPCR family of receptors. Family members are characterized by an extended extracellular region with a variable number of protein domains ...
,
LPHN2 Latrophilin 2 is a protein that in humans is encoded by the ''ADGRL2'' gene. This gene encodes a member of the latrophilin subfamily of G-protein coupled receptors (GPCR). Latrophilins may function in both cell adhesion and signal transduction. I ...
,
LPHN3 Latrophilin 3 is a protein that in humans is encoded by the ''ADGRL3'' gene. Function This gene encodes a member of the latrophilin subfamily of G protein-coupled receptors (GPCR). Latrophilins may function in both cell adhesion and signal tr ...
, and ETL. Group II consists of
CD97 Cluster of differentiation 97 is a protein also known as BL-Ac 2encoded by the ''ADGRE5'' gene. CD97 is a member of the adhesion G protein-coupled receptor (GPCR) family. Adhesion GPCRs are characterized by an extended extracellular region oft ...
,
EMR1 EGF-like module-containing mucin-like hormone receptor-like 1 also known as F4/80 is a protein encoded by the ''ADGRE1'' gene. EMR1 is a member of the adhesion GPCR family characterized by an extended extracellular region containing EGF-like ...
,
EMR2 EGF-like module-containing mucin-like hormone receptor-like 2 also known as CD312 (cluster of differentiation 312) is a protein encoded by the ''ADGRE2'' gene. EMR2 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an ...
,
EMR3 EGF-like module-containing mucin-like hormone receptor-like 3 is a protein encoded by the ''ADGRE3'' gene. EMR3 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-term ...
, and
EMR4 The EGF module-containing Mucin-like hormone Receptors (EMRs) are closely related subgroup of G protein-coupled receptors (GPCRs). These receptors have a unique hybrid structure in which an extracellular epidermal growth factor (EGF)-like dom ...
. Group III consists of
GPR123 Probable G-protein coupled receptor 123 is a protein that in humans is encoded by the ''GPR123'' gene. It is a member of the adhesion-GPCR Adhesion G protein-coupled receptors (adhesion GPCRs) are a class of 33 human protein Receptor (biochemi ...
,
GPR124 Probable G-protein coupled receptor 124 is a protein that in humans is encoded by the ''GPR124'' gene. It is a member of the adhesion-GPCR Adhesion G protein-coupled receptors (adhesion GPCRs) are a class of 33 human protein Receptor (bioche ...
, and
GPR125 Adhesion G-protein coupled receptor A3 (ADGRA3), also known as GPR125, is an adhesion GPCR that in humans is encoded by the ''Adgra3'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The mo ...
. Group IV consists of
CELSR1 Cadherin EGF LAG seven-pass G-type receptor 1 also known as flamingo homolog 2 or cadherin family member 9 is a protein that in humans is encoded by the ''CELSR1'' gene. Function The protein encoded by this gene is a member of the flamingo su ...
,
CELSR2 Cadherin EGF LAG seven-pass G-type receptor 2 is a protein that in humans is encoded by the ''CELSR2'' gene. The protein encoded by this gene is a member of the flamingo subfamily, part of the cadherin superfamily. The flamingo subfamily consis ...
, and
CELSR3 Cadherin EGF LAG seven-pass G-type receptor 3 is a protein that in humans is encoded by the ''CELSR3'' gene. The protein encoded by this gene is a member of the flamingo subfamily, part of the cadherin superfamily. The flamingo subfamily consist ...
. Group V consists of
GPR133 Probable G-protein coupled receptor 133 is a protein that in humans is encoded by the ''GPR133'' gene. This gene encodes a member of the adhesion-GPCR family of receptors. Family members are characterized by an extended extracellular region with ...
and
GPR144 Probable G-protein coupled receptor 144 is a protein that in humans is encoded by the ''GPR144'' gene. This gene encodes a member of the adhesion-GPCR Adhesion G protein-coupled receptors (adhesion GPCRs) are a class of 33 human protein Rece ...
. Group VI consists of
GPR110 Probable G-protein coupled receptor 110 is a protein that in humans is encoded by the ''GPR110'' gene. This gene encodes a member of the adhesion-GPCR receptor family. Family members are characterized by an extended extracellular region with a var ...
, GPR111,
GPR113 GPR113 is a gene that encodes the Probable G-protein coupled receptor 113 protein. Gene The human GPR113 gene is located on chromosome 2 (2p23.3). This gene spans the length of a 38.65kb region from base 26531041 to 26569685 on the negative st ...
,
GPR115 Probable G-protein coupled receptor 115 is a protein that in humans is encoded by the ''GPR115'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotide ...
, and GPR116. Group VII consists of
BAI1 Brain-specific angiogenesis inhibitor 1 is a protein that in humans is encoded by the ''BAI1'' gene. It is a member of the adhesion-GPCR family of receptors. Function Angiogenesis is controlled by a local balance between stimulators and inhi ...
,
BAI2 Brain-specific angiogenesis inhibitor 2 is a protein that in humans is encoded by the ''BAI2'' gene. It is a member of the adhesion-GPCR family of receptors. BAI1 Brain-specific angiogenesis inhibitor 1 is a protein that in humans is encoded ...
, and
BAI3 Brain-specific angiogenesis inhibitor 3 is a protein that in humans is encoded by the ''BAI3'' gene. BAI1, a p53-target gene, encodes brain-specific angiogenesis inhibitor, a seven-span transmembrane protein and is thought to be a member of the ...
. Group VIII consists of
GPR56 G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ''ADGRG1'' gene. GPR56 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal prote ...
, GPR97,
GPR112 G protein-coupled receptor 112 is a protein encoded by the ''ADGRG4'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcrib ...
,
GPR114 G protein-coupled receptor 114 is a protein encoded by the ''ADGRG5'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcrib ...
, GPR126, and
GPR64 G protein-coupled receptor 64 also known as HE6 is a protein encoded by the ''ADGRG2'' gene. GPR64 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein ...
. Two additional adhesion GPCRs do not fit into these groups:
VLGR1 ADGRV1, also known as G protein-coupled receptor 98 (GPR98) or Very Large G-protein coupled receptor 1 (VLGR1), is a protein that in humans is encoded by the ''GPR98'' gene. Several alternatively spliced transcripts have been described. The adhe ...
and GPR128.


Non-humans and evolution

Adhesion GPCRs are found in
fungi A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified as one ...
. They are believed to have evolved from the cAMP receptor family, arising approximately 1275 million years ago before the split of Unikonts from a common ancestor. Several fungi have novel adhesion GPCRs that have both short, 2–66 amino acid residues, and long, 312–4202 amino acid residues. Analysis of fungi showed that there were no
secretin receptor family Secretin receptor family (class B GPCR subfamily) consists of secretin receptors regulated by peptide hormones from the glucagon hormone family. The family is different from adhesion G protein-coupled receptors. The secretin-receptor family of G ...
GPCRs, which suggests that they evolved from adhesion GPCRs in a later organism. Genome analysis of the
Teleost Teleostei (; Ancient Greek, Greek ''teleios'' "complete" + ''osteon'' "bone"), members of which are known as teleosts (), is, by far, the largest group of ray-finned fishes (class Actinopterygii), with 96% of all neontology, extant species of f ...
''
Takifugu rubripes ''Takifugu rubripes'', commonly known as the Japanese puffer, Japanese pufferfish, Tiger puffer, or torafugu (), is a pufferfish in the genus '' Takifugu''. It is distinguished by a very small genome that has been fully sequenced because of its ...
'' has revealed that it has only two adhesion GPCRs that showed homology to Ig-hepta/ GPR116. While the
Fugu Fugu (; ; ) in Japanese language, Japanese, ''bogeo'' (; 鰒魚) or ''bok'' () in Korean language, Korean, and ''hétún'' () in Standard Modern Chinese refers to tetraodontidae, pufferfish, normally of the genus ''Takifugu'', ''Lagocephalus'', o ...
genome is relatively compact and limited with the number of adhesion GPCRs, ''
Tetraodon nigroviridis ''Dichotomyctere nigroviridis'' ( syn. ''Tetraodon nigroviridis'') or the green spotted puffer is a species of pufferfish. It is found across South and Southeast Asia in coastal freshwater, but survives the longest in brackish to saltwater, and b ...
'', another species of
puffer fish Tetraodontidae is a family of marine and freshwater fish in the order Tetraodontiformes. The family includes many familiar species variously called pufferfish, puffers, balloonfish, blowfish, blowers, blowies, bubblefish, globefish, swellfish, ...
, has considerably more, totaling 29 adhesion GPCRs.


Ligands

A majority of the adhesion GPCRs are orphan receptors and work is underway to de-orphanize many of these receptors. Adhesion GPCRs get their name from their N-terminal domains that have adhesion-like domains, such as EGF, and the belief that they interact cell to cell and cell to extra cellular matrix. While ligands for many receptors are still not known, researchers are utilizing drug libraries to investigate compounds that can activate GPCRs and using these data for future ligand research. One adhesion GPCR,
GPR56 G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ''ADGRG1'' gene. GPR56 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal prote ...
, has a known ligand,
collagen III Type III Collagen is a homotrimer, or a protein composed of three identical peptide chains (monomers), each called an alpha 1 chain of type III collagen. Formally, the monomers are called collagen type III, alpha-1 chain and in humans are encode ...
, which is involved in neural migration inhibition.
GPR56 G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ''ADGRG1'' gene. GPR56 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal prote ...
has been shown to be the cause of
polymicrogyria Polymicrogyria (PMG) is a condition that affects the development of the human brain by multiple small gyri ( microgyri) creating excessive folding of the brain leading to an abnormally thick cortex. This abnormality can affect either one region of ...
in humans and may play a role in cancer
metastasis Metastasis is a pathogenic agent's spreading 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, ...
. The binding of collagen III to GPR56 occurs on the
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
and has been narrowed down to a short stretch of amino acids. The N-terminus of GPR56 is naturally
glycosylated Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
, but this glycosylation is not necessary for collagen III binding. Collagen III, results in GPR56 to signal through Gα12/13 activating
RhoA Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the ''RHOA'' gene. While the effects of RhoA activity are not all well known, it is ...
.


Signaling

Adhesion GPCRs appear capable to follow standard
GPCR 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 ...
signaling modes and signal through
Gαs The Gs alpha subunit (Gαs, Gsα) is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein. Gsα is the founding m ...
,
Gαq Gq protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gq/11 (Gq/G11) family or Gq/11/14/15 family to include closely related family members. G alpha subunits may be referred ...
,
Gαi Gi protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gi/o (Gi /Go ) family or Gi/o/z/t family to include closely related family members. G alpha subunits may be referred ...
, and Gα12/13. As of today, many of the adhesion GPCRs are still orphan receptors and their signalling pathways have not been identified. Research groups are working to elucidate the downstream signaling molecules utilizing several methods, including chemical screens and analysis of second messenger levels in over-expressed cells. Adding drugs ''in vitro'', while the cells are over-expressing an adhesion GPCR, has allowed the identification of the molecules activating the GPCR and the second messengers being utilized.
GPR133 Probable G-protein coupled receptor 133 is a protein that in humans is encoded by the ''GPR133'' gene. This gene encodes a member of the adhesion-GPCR family of receptors. Family members are characterized by an extended extracellular region with ...
signals through
Gαs The Gs alpha subunit (Gαs, Gsα) is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein. Gsα is the founding m ...
to activate
adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...
. It has been shown that overexpressing GPCRs ''in vitro'' can result in receptor activation in the absence of a ligand or agonist. By over expressing GPR133 ''in vitro'', an elevation in reporter genes and cAMP was observed. Signaling of the overexpressed GPR133 did not require an N-terminus or GPS cleavage. Missense mutations in the 7TM region resulted in loss of signalling. The latrophilin homolog
LPHN1 Latrophilin 1 is a protein that in humans is encoded by the ''ADGRL1'' gene. It is a member of the adhesion-GPCR family of receptors. Family members are characterized by an extended extracellular region with a variable number of protein domains ...
was shown in ''
C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' ( ...
'' to require a GPS for signaling, but cleavage at the GPS site was not necessary. Furthermore, having a shortened 7 transmembrane domain, but with an intact GPS domain, resulted in a loss of signaling. This suggests that having both the GPS and 7 transmembrane domain intact is involved in signaling and that the GPS site could act as or be a necessary part of an endogenous ligand. GPR56 has been shown to be cleaved at the GPS site and then remain associated with the
7TM 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 ...
domain. In a study where the N-terminus was removed up to N342 (the start of the GPS), the receptor became constitutively active and an up regulation of Gα12/13 was seen. When receptors are active, they are ubiquitinated and GPR56 lacking an N-terminus was highly ubiquitinated.


Cleavage

Many adhesion GPCRs undergo proteolytic events posttranslationally at highly conserved Cys-rich motifs known as GPCR proteolysis sites (GPS), located next to the first transmembrane region. This site is called the HL-S(T) site. Once this protein is cleaved, the pieces are expressed at the cell surface as a heterodimer. This cleavage is thought to happen from within the protein itself, through the conserved
GAIN domain The GAIN domain ( G-protein-coupled receptor (GPCR) autoproteolysis-inducing domain) is a protein domain found in a number of cell surface receptors, including adhesion-GPCRs and polycystic kidney disease proteins PKD1 and PKD2 Polycystin-2 (P ...
. This process seems to be similar to those found in other auto-proteolytic proteins such as the Ntn hydrolases and
hedgehog A hedgehog is a spiny mammal of the subfamily Erinaceinae, in the eulipotyphlan family Erinaceidae. There are 17 species of hedgehog in five genera found throughout parts of Europe, Asia, and Africa, and in New Zealand by introduction. The ...
proteins.


Domains

One characteristic of adhesion GPCRs is their extended extracellular region. This region is modular in nature, often possessing a variety of structurally defined protein domains and a membrane proximal
GAIN Gain or GAIN may refer to: Science and technology * Gain (electronics), an electronics and signal processing term * Antenna gain * Gain (laser), the amplification involved in laser emission * Gain (projection screens) * Information gain in de ...
domain. In the aptly named Very Large G protein-coupled Receptor 1
VLGR1 ADGRV1, also known as G protein-coupled receptor 98 (GPR98) or Very Large G-protein coupled receptor 1 (VLGR1), is a protein that in humans is encoded by the ''GPR98'' gene. Several alternatively spliced transcripts have been described. The adhe ...
the extracellular region extends up to almost 6000 amino acids. Human adhesion GPCRs possess domains including EGF-like (),
Cadherin Cadherins (named for "calcium-dependent adhesion") are cell adhesion molecules important in forming adherens junctions that let cells adhere to each other. Cadherins are a class of type-1 transmembrane proteins, and they depend on calcium (Ca2+) ...
(),
thrombospondin Thrombospondins (TSPs) are a family of secreted glycoproteins with antiangiogenic functions. Due to their dynamic role within the extracellular matrix they are considered matricellular proteins. The first member of the family, thrombospondin 1 ...
(),
Immunoglobulin An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
(),
Pentraxin Pentraxins (PTX), also known as pentaxins, are an evolutionary conserved family of proteins characterised by containing a pentraxin protein domain. Proteins of the pentraxin family are involved in acute immunological responses. They are a cl ...
(), Calx-beta () and
Leucine-rich repeats A leucine-rich repeat (LRR) is a protein structural motif that forms an α/β horseshoe fold. It is composed of repeating 20–30 amino acid stretches that are unusually rich in the hydrophobic amino acid leucine. These tandem repeats common ...
(). In non-vertebrate species multiple other structural motifs including
Kringle Kringle (, ) is a Northern European pastry, a variety of pretzel. Pretzels were introduced by Roman Catholic monks in the 13th century in Denmark, and from there they spread throughout Scandinavia and evolved into several kinds of sweet, salty o ...
, Somatomedin B (), SRCR () may be contained with the extracellular region. Since many of these domains have been demonstrated to mediate protein-protein interactions within other proteins, they are believed to play the same role in adhesion GPCRs. Indeed, many ligands have been discovered for adhesion GPCRs (see ligands section). Many of the adhesion GPCR possess long stretches of amino acids with little homology to known protein domains suggesting the possibility of new structural domains being elucidated within their extracellular regions.


Roles


Immune system

A number of adhesion GPCRs may have important roles within the immune system. In particular, members the EGF-TM7 subfamily which possess N-terminal EGF-like domains are predominantly restricted to leukocytes suggesting a putative role in immune function. The human EGF‑TM7 family is composed of CD97, EMR1 (F4/80 receptor orthologue) EMR2, EMR3 and EMR4 (a probable
pseudogene Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Pseudogenes can be formed from both protein-coding genes and non-coding genes. In the case of protein-coding genes, most pseudogenes arise as superfluous copies of fun ...
in humans). The human-restricted EMR2 receptor, is expressed by myeloid cells including
monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...
,
dendritic cells A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
and
neutrophils Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in different ...
has been shown to be involved in the activation and migration of human neutrophils and upregulated in patients with systemic inflammatory response syndrome (SIRS). Details of EMR1, CD97 needed. The adhesion‑GPCR brain angiogenesis inhibitor 1 (BAI1) acts as a phosphatidylserine receptor playing a potential role in the binding and clearance of apoptotic cells, and the phagocytosis of Gram-negative bacteria. GPR56 has been shown to a marker for inflammatory NK cell subsets and to be expressed by cytotoxic lymphocytes.


Neuronal development

GPR126 is necessary for
Schwann cell Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include Satellite glial cell, satellite ...
myelination. Knockouts of this adhesion GPCR in both ''
Danio rerio The zebrafish (''Danio rerio'') is a species of freshwater ray-finned fish belonging to the family Danionidae of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (a ...
'' and ''
Mus musculus The house mouse (''Mus musculus'') is a small mammal of the rodent family Muridae, characteristically having a pointed snout, large rounded ears, and a long and almost hairless tail. It is one of the most abundant species of the genus ''Mus (genu ...
'' result in an arrest at the promyelinating stage. Schwann cells arise from the neural crest, which migrates to peripheral nerves to form either myelinating or non-myelinating cells. In GPR126 knockouts, these precursor cells develop to the promyelinating stage, where they have wrapped approximately 1.5 times. Myelination is arrested at the promyelinating stage and in fish no
myelin basic protein Myelin basic protein (MBP) is a protein important in the process of myelination of nerves in the nervous system. The myelin sheath is a multi-layered membrane, unique to the nervous system, that functions as an insulator to greatly increase the ve ...
can be detected. In fish this can be rescued by adding forskolin during development, which rescues
myelin basic protein Myelin basic protein (MBP) is a protein important in the process of myelination of nerves in the nervous system. The myelin sheath is a multi-layered membrane, unique to the nervous system, that functions as an insulator to greatly increase the ve ...
expression.


Bone marrow and hematapoietic stem cells

GPR56 G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ''ADGRG1'' gene. GPR56 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal prote ...
may play a role in the interactions between bone marrow and hematopoietic stem cells.


Disease

Loss of function mutations have been shown in a number of adhesion GPCRs, including GPR56, GPR126 and VLRG1. Many mutations affect function via decreased cell surface expression or inhibition of autoproteolysis within the GAIN domain. Mutations in GPR56 result in
bilateral frontoparietal polymicrogyria Bilateral frontoparietal polymicrogyria is a genetic disorder with autosomal recessive inheritance that causes a cortical malformation. Our brain has folds in the cortex to increase surface area called gyri and patients with polymicrogyria have a ...
in humans, characterized by abnormal neuronal migration and surface ectopias., Variants of GPR126 have been associated with adolescent idiopathic
scoliosis Scoliosis (: scolioses) is a condition in which a person's Vertebral column, spine has an irregular curve in the coronal plane. The curve is usually S- or C-shaped over three dimensions. In some, the degree of curve is stable, while in others ...
, as well as being responsible for severe
arthrogryposis Arthrogryposis (AMC) describes congenital joint contracture in two or more areas of the body. It derives its name from Greek, literally meaning 'curving of joints' (', 'joint'; ', late Latin form of late Greek ', 'hooking'). Children born with one ...
multiplex congenita. Gain of function mutations within the GAIN domain of EMR2 have been shown to result in excessive degranulation by mast cells resulting in vibratory
urticaria Hives, also known as urticaria, is a kind of skin rash with red or flesh-colored, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and typically ...
.


References

{{G protein-coupled receptors Adhesion G protein-coupled receptors Cell adhesion proteins G protein-coupled receptors Cell signaling Signal transduction