G protein-coupled receptor 15 is a
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 ...
that in humans is encoded by the GPR15
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 ...
.
GPR15 is a class A orphan
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 ...
(heterotrimeric guanine nucleotide-binding protein, GPCR). The ''GPR15'' gene is localized at chromosome 3q11.2-q13.1.
It is found in epithelial cells,
synovial macrophages, endothelial cells
and lymphocytes especially T cells.
From the mRNA sequence a 40.8 kD molecular weight of GPR15 is proposed. In an epithelial tumour cell line (HT-29), however, a 36 kD band, composed of GPR15 and galactosyl ceramide, was detected.
Protein expression in lymphocytes is strongly associated with hypomethylation of its gene.
Tissue distribution
High gene expression was described for colonic mucosa, small bowel mucosa, liver and spleen. Moderate gene expression was found in blood, lymph node, thymus, testis and prostate.
In peripheral blood, GPR15 is mainly found on T cells, especially on
CD4+
T helper cells
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
, and less prominent on
B cells
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 o ...
.
By immunohistochemistry GPR15 is found specifically in glandular cells of the stomach, α-cells of islet of Langerhans in pancreas, surface epithelium of small intestine and colon, hepatocytes in liver, tubular epithelium of the kidney and in diverse tumour tissues such as
glioblastoma
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...
,
melanoma, small cell lung carcinoma or colon carcinoma.
Function
The overall physiological role remains elusive. It seems to play a role in homing of single T cell types to the colon. In human, GPR15 controls together with α4β7-
integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle ...
the homing of effector T cells to the inflamed gut of ulcerative colitis.
With respect to the homing of GPR15-expressing immune cells to the colon there are divergent mechanisms between human and rodents like mouse.
Ligands
There are at least two endogenous ligand found recently. One ligand encoded by the human gene ''
C10orf99'' was identified as a robust marker for psoriasis whose abundance decreased after therapeutic treatment with anti-interleukin-17 antibody. Transcripts of ''C10orf99'' are abundant in cervix and colon. It is currently unknown whether C10orf99 causes disease symptoms or is the consequence of a disturbed epithelial barrier. It does not act as a chemotactic agent but rather decrease T cell migration suggesting a mechanism of heterologous receptor desensitization.
The second ligand is a fragment of
thrombomodulin
Thrombomodulin (TM), CD141 or BDCA-3 is an integral membrane protein expressed on the surface of endothelial cells and serves as a cofactor for thrombin. It reduces blood coagulation by converting thrombin to an anticoagulant enzyme from a procoag ...
exerting anti-inflammatory function in mice.
Clinical significance
Human GPR15 was originally cloned as a co-receptor for
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 ...
or the simian immunodeficiency virus.
HIV-induced activation of GPR15 in enterocytes seems to cause HIV enteropathy accompanied with diarrhea and lipid malabsorption.
In inflammatory bowel diseases (IBD) such as
Crohn’s disease
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distensio ...
and
ulcerative colitis
Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and ...
the proportion of GPR15-expressing cells among regulatory T cells is slightly increased in peripheral blood.
In mouse, GPR15-deficient mice were prone to develop severe large intestine inflammation, which was rescued by the transfer of GPR15-sufficient T regs.
Lifestyle
Chronic tobacco smoking is a very strong inducer of GPR15-expressing T cells in peripheral blood. Although the proportion of GPR15-expressing cells among T-cells in peripheral blood is a high sensitive and specific biomarker for chronic tobacco smoking
it does not indicate a disturbed homeostasis in the lung.
References
Further reading
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G protein-coupled receptors
{{transmembranereceptor-stub