Cysteinyl leukotriene receptor 2, also termed CYSLTR2, is a receptor for cysteinyl leukotrienes (LT) (see
leukotrienes#Cysteinyl leukotrienes). CYSLTR2, by binding these cysteinyl LTs (CysLTs; viz,
LTC4
Leukotriene C4 (LTC4) is a leukotriene. LTC4 has been extensively studied in the context of allergy and asthma. In cells of myeloid origin such as mast cells, its biosynthesis is orchestrated by translocation to the nuclear envelope along with c ...
,
LTD4
Leukotriene D4 (LTD4) is one of the leukotrienes. Its main function in the body is to induce the contraction of smooth muscle, resulting in bronchoconstriction and vasoconstriction. It also increases vascular permeability. LTD4 is released by bas ...
, and to a much lesser extent,
LTE4
Leukotriene E4 (LTE4) is a cysteinyl leukotriene involved in inflammation. It is known to be produced by several types of white blood cells, including eosinophils, mast cells, tissue macrophages, and basophils, and recently was also found to be ...
) contributes to mediating various allergic and hypersensitivity reactions in humans. However, the first discovered receptor for these CsLTs,
cysteinyl leukotriene receptor 1
Cysteinyl leukotriene receptor 1, also termed CYSLTR1, is a receptor for cysteinyl leukotrienes (LT) (see leukotrienes#Cysteinyl leukotrienes). CYSLTR1, by binding these cysteinyl LTs (CysLTs; viz, LTC4, LTD4, and to a much lesser extent, LTE4) c ...
(CysLTR1), appears to play the major role in mediating these reactions.
Gene
The human gene maps to the long arm of chromosome 13 at position 13q14, a chromosomal region that has long been linked to asthma and other allergic diseases.
The gene consists of four exons with all introns located in the genes'
5' UTR
The 5′ untranslated region (also known as 5′ UTR, leader sequence, transcript leader, or leader RNA) is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of ...
region and the entire coding region located in the last exon. CysLTR2'' encodes 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, respo ...
composed of 347
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s and shows only modest similarity to the ''CysLTR1'' gene in that its protein shares only 31% amino acid identity with the CysLTR1 protein.
Receptor
CySLTR2
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
is co-expressed along with CysLRR1 in human blood
eosinophil
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
s and
platelet
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 ini ...
s, and tissue
mast cell
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 par ...
s,
macrophage
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 cel ...
s, airway
epithelial cell
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 intercellula ...
s, and vascular
endothelial cell
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 ...
s. It is also expressed without CysLTR1 throughout the heart, including
Purkinje cell
Purkinje cells, or Purkinje neurons, are a class of GABAergic inhibitory neurons located in the cerebellum. They are named after their discoverer, Czech people, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839.
Stru ...
s,
adrenal gland
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which ...
, and brain as well as some vascular endothelial, airway epithelial, and smooth muscle cells.
CysLTR2, similar to CysLTR1, is a
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 ...
that links to and when bound to its CysLT
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
s activates the
Gq alpha subunit
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 ...
and/or
Ga subunit of its coupled G protein, depending or the cell type. Acting through these G proteins and their subunits, ligand-bound CysLTR1 activates a series of pathways that lead to cell function (see
Gq alpha subunit#function and
Ga subunit#function for details); the order of potency of the cysLTs in stimulating CysLTR2 is LTD4=LTC4>LTE4 with LTE4 probably lacking sufficient potency to have much activity that operates through CysLTR1 in vivo. By comparison, the stimulating potencies of these CysLTs for CysLTR1 is LTD4>LTC4>LTE4 with LTD4 showing 10-fold greater potency on CysLTR1 than CysLTR2.
Perhaps related to this difference in CysLT sensitivities, cells co-expressing CysLTR2 and CysLTR1 may exhibit lower sensitivity to LTD4 than do cells expressing only CysLTR1; in consequence, CysLTR2 has been suggested to dampen CysLTR1's activities.
In addition to CysLTR1,
GPR99
2-Oxoglutarate receptor 1 (OXGR1), also known as cysteinyl leukotriene receptor E (CysLTE) and GPR99, is a protein that in humans is encoded by the (also termed ''GPR99'') gene. The Gene has recently been nominated as a receptor not only for 2-ox ...
(also termed the oxoglutarate receptor or, sometimes, CysLTR3) appears to be an important receptor for CysLTs, particularly for LTE4: the CystLTs show relative potencies of LTE4>LTC4>LTD4 in stimulating GPR99-bearing cells and GPR99-deficient mice exhibit a dose-dependent loss of vascular permeability responses in skin to LTE4 but not to LTC4 or LTD4.
Other studies on model cells for allergy have defined
GPR17
Uracil nucleotide/cysteinyl leukotriene receptor is a G protein-coupled receptor that in humans is encoded by the ''GPR17'' gene located on chromosome 2 at position q21. The actual activating ligands for and some functions of this receptor are dis ...
(also termed the uracil nucleotide/cysteinyl leukotriene receptor) as a receptor not only
uracil nucleotides
Uracil () ( symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced ...
but also for CysLTs, with CysLTs having the following potencies LTD4>LTC4>LTE4 in stimulating GPR17-bearing cells. However, recent studies also working with model cells involved in allergy find that GPR17-bearing cells do not respond to these CysLTs (or uracil nucleotides). Rather, they find that: a) cells expressing both CysLTR1 and GPR17 receptors exhibit a marked reduction in binding and responding to LTD4 and b) mice lacking GPR17 are hyper-responsive to
igE
Immunoglobulin E (IgE) is a type of antibody (or immunoglobulin (Ig) " isotype") that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains (ε chain) and two light chains, with the ε c ...
in a model for passive cutaneous anaphylaxis. The latter studies conclude that GPR17 acts to inhibit CysLTR1.
Finally, and in striking contrast to these studies, repeated studies on neural tissues find that
Oligodendrocyte progenitor cell
Oligodendrocyte progenitor cells (OPCs), also known as oligodendrocyte precursor cells, NG2-glia, O2A cells, or polydendrocytes, are a subtype of glia in the central nervous system named for their essential role as precursors to oligodendrocytes. ...
s express GPR17 and respond through this receptor to LTC4, LTD4, and certain purines (see
GPR17#Function).
CysLTR2 inhibitors
There are as yet no selective inhibitors of CysLTR2 that are in clinical use (see Clinical significance section below). However, Gemilukast (ONO-6950) reportedly inhibits both CysLTR1 and CysLTR2. The drug is currently being evaluated in phase II trials for the treatment of asthma.
CysLTR2 polymorphism
Polymorphism in the ''CysLTR2'' gene resulting in a single amino acid substitution, M201V (i.e. amino acid methionine changed for valine at the 201 position of CysLTR2 protein) has been negatively associated in
Transmission disequilibrium test The transmission disequilibrium test (TDT) was proposed by Spielman, McGinnis and Ewens (1993) as a family-based association test for the presence of genetic linkage between a genetic marker and a trait. It is an application of McNemar's test.
A ...
ing with the inheritance of asthma in separate populations of: a) white and African-Americans from 359 families with a high prevalence of asthma in Denmark and Minnesota, USA, and b) 384 families with a high prevalence of asthma from the Genetics of Asthma International Network. The M201V CysLTR2 variant exhibits decreased responsiveness to LTD4 suggesting that this hypo-responsiveness underlies its asthma transmission-protecting effect.
A -1220A>C (i.e. nucleotide adenine substituted for cytosine at position 1220 upstream from the transcription start site)
gene polymorphism
A gene is said to be polymorphic if more than one allele occupies that gene's locus within a population. In addition to having more than one allele at a specific locus, each allele must also occur in the population at a rate of at least 1% to gen ...
variant in
intron
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. ...
III the upstream region of CysLTR2 has been associated significantly with development of asthma in a Japanese population; the impact of this polymorphism on the genes expression or product has not been determined.
These results suggest that CYSLTR2 contributes to the etiology and development asthma and that drugs targeting CYSLTR2 may work in a manner that differs from those of CYSLTR1 antagonists.
Clinical significance
The CysLT-induced activation of CysLTR2 induces many of the same in vitro responses of cells involved in allergic reactions as well as the in vivo allergic responses in animal models as that induced by CysLT-induced CysLTR1 (see
Cysteinyl leukotriene receptor 1#Receptor.
However, CysLT2 requires 10-fold higher concentrations of LTD4, the most potent cysLT for CysLTR1, to activate CysLTR2. Furthermore, the allergic and hypersensitivity responses of humans and animal models are significantly reduced by chronic treatment with
Montelukast
Montelukast, sold under the brand name Singulair among others, is a medication used in the maintenance treatment of asthma. It is generally less preferred for this use than inhaled corticosteroids. It is not useful for acute asthma attacks. Ot ...
,
Zafirlukast
Zafirlukast is an orally administered leukotriene receptor antagonist (LTRA) used for the chronic treatment of asthma. While zafirlukast is generally well tolerated, headache and stomach upset often occur. Some rare side effects can occur, which ...
, and
Pranlukast
Pranlukast (brand name Onon, オノン) is a cysteinyl leukotriene receptor-1 antagonist. This drug works similarly to Merck & Co.'s montelukast (Singulair). It is widely used in Japan.
Medications of this class, which go under a variety of nam ...
, drugs which are selective
receptor antagonists
A receptor antagonist is a type of Receptor (biochemistry), receptor ligand (biochemistry), ligand or drug that blocks or dampens a biological response by binding to and blocking a Receptor (biochemistry), receptor rather than activating it like ...
of CysLTR1 but not CysLTR2.
Models of allergic reactions in Cysltr2-deficient mice as well as in a human
mast cell
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 par ...
line indicate that mouse Cysltr2 and its human
homolog
In biology, homology is similarity due to shared ancestry between a pair of structures or genes in different taxa. A common example of homologous structures is the forelimbs of vertebrates, where the wings of bats and birds, the arms of prima ...
CysLTR2 act to inhibit Cysltr1 and CysLTR1, respectively, and therefore suggest that CysLTR2 may similarly inhibit CysLTR1 in human allergic diseases.
The role of CysLTR2 in the allergic and hypersensitivity diseases of humans must await the development of selective CysLTR2 inhibitors.
See also
*
Cysteinyl leukotriene receptor 1
Cysteinyl leukotriene receptor 1, also termed CYSLTR1, is a receptor for cysteinyl leukotrienes (LT) (see leukotrienes#Cysteinyl leukotrienes). CYSLTR1, by binding these cysteinyl LTs (CysLTs; viz, LTC4, LTD4, and to a much lesser extent, LTE4) c ...
*
Eicosanoid receptor
Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that bind and respond to eicosanoid signaling molecules. Eicosanoids are rapidly metabolized to inactive products and therefore are short-lived. Acc ...
*
GPR99
2-Oxoglutarate receptor 1 (OXGR1), also known as cysteinyl leukotriene receptor E (CysLTE) and GPR99, is a protein that in humans is encoded by the (also termed ''GPR99'') gene. The Gene has recently been nominated as a receptor not only for 2-ox ...
References
Further reading
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External links
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{{Use dmy dates, date=April 2017
G protein-coupled receptors