The Prostacyclin receptor, also termed the prostaglandin I2 receptor or just IP, is a
receptor
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
belonging to the
prostaglandin (PG) group of receptors. IP binds to and mediates the biological actions of
prostacyclin (also termed Prostaglandin I
2, PGI
2, or when used as a drug, epoprostenol). IP is encoded in humans by the ''PTGIR''
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 ...
. While possessing many functions as defined in animal model studies, the major clinical relevancy of IP is as a powerful vasodilator: stimulators of IP are used to treat severe and even life-threatening diseases involving pathological
vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...
.
Gene
The gene is located on human chromosome 19 at position q13.32 (i.e. 19q13.32), contains 6 exons, and codes for a
G protein coupled receptor (GPCR) of the rhodopsin-like receptor family, Subfamily A14 (see
rhodopsin-like receptors#Subfamily A14).
Expression
IP is most highly expressed in brain and
thymus
The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or '' T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders ...
and is readily detected in most other tissues. It is found throughout the vascular network on
endothelium
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 ve ...
and
smooth muscle cells.
Ligands
Activating ligands
Standard
prostanoid
Prostanoids are active lipid mediators that regulate inflammatory response. Prostanoids are a subclass of eicosanoids consisting of the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes (mediators of vasocons ...
s have the following relative efficacies as
receptor ligands in binding to and activating IP: PGI
2>>
PGD2=
PGE2=
PGF2α PGF may refer to:
* Paternal grandfather
* Patterson–Gimlin film, purporting to show Bigfoot
* IATA code of Perpignan–Rivesaltes Airport, France
* Placental growth factor, a human gene
* Vector graphics language in the PGF/TikZ pair
* Precis ...
>
TXA2
Thromboxane A2 (TXA2) is a type of thromboxane that is produced by activated platelets during hemostasis and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by act ...
. In typical binding studies, PGI
2 has one-half of its maximal binding capacity and cell-stimulating actions at ~1
nanomolar whereas the other prostaglandins are >50-fold to 100-fold weaker than this. However, PGI
2 is very unstable, spontaneously converting to a far less active derivative
6-keto-PGF1 alpha within 1 minute of its formation. This instability makes defining the exact affinity of PGI
2 for IP difficult. It also makes it important to have stable synthetic analogs of PGI
2 for clinical usage. The most potent of these
receptor agonists
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
for binding to and activating IP are
iloprost, taprostene, and esuberaprost which have
Kd values (i.e. concentrations which bind to half of available IP receptors) in the low nano
mole/liter range (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=345/).
Inhibiting ligands
Several synthetic compounds bind to, but do not activate, IP and thereby inhibit its activation by the activating ligands just described. These
receptor antagonists include RO1138452, RO3244794, TG6-129, and BAY-73-1449, all of which have K
d values for IP at or beneath low nanomol/liter levels (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=345/).
Mechanism of cell activation
IP is classified as a relaxant type of prostenoid receptor based on its ability, upon activation, to relax certain pre-contracted smooth muscle preparations and smooth muscle-containing tissues such as those of pulmonary arteries and veins.
When bound to PGI
2 or other of its agonists, IP stimulates one or more of three types of
G protein complexes, depending on cell type: a)
Gs alpha subunit-
Gβγ complexes which release Gs that then stimulates
adenyl cyclase to raise intracellular levels of
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
and thereby activate cAMP-regulated protein kinases A-dependent
cell signaling pathways (see
PKA
PKA may refer to:
* Professionally known as:
** Pen name
** Stage persona
* p''K''a, the symbol for the acid dissociation constant at logarithmic scale
* Protein kinase A, a class of cAMP-dependent enzymes
* Pi Kappa Alpha, the North-American so ...
); b)
Gq alpha subunit-Gβγ complexes which release Gq that then stimulates other cell signaling pathways (e.g.
phospholipase C/
IP3/cell
Ca2+ mobilization/
diacylglycerol/
protein kinase Cs,
calmodulin-modulated
myosin light chain kinase,
RAF/
MEK/
Mitogen-activated protein kinases, PKC/Ca
2+/
Calcineurin/
Nuclear factor of activated T-cells; and
EGF cellular receptors; and c)
Gi alpha subunit-Giβγ) complexes which releases Gi that then simulates
phospholipase C to cleave phosphatidylinositol triphosphate into
inositol triphosphate that raises intracellular CaCa
2 levels thereby regulating
Calcium signaling pathways and
diacylglycerol that activates certain
protein kinase C enzymes )that phosphorylate and thereby regulate target proteins involved in cell signaling (see
Protein kinase C#Function). Studies suggest that stimulation of Gsβγ complexes is required for activation of the Gqβγ- and Giβγ-dependent pathways.
In certain cells, activation of IP also stimulates
G12/G13-Gβγ G proteins to activate the
Rho family of GTPases signaling proteins and
Gi-Gβγ G proteins to activate
Raf/MEK/mitogen-activated kinase pathways.
Functions
Studies using animals genetically engineered to lack IP and examining the actions of EP4 receptor agonists in animals as well as animal and human tissues indicate that this receptor serves various functions. It has been regarded as the most successful therapeutic target among the 9 prostanoid receptors.
Platelets
IP
gene knockout mice (i.e. IP(-/-) mice) exhibit increased tendency 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 (th ...
in response to experimentally-induced
Endothelium
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 ve ...
, a result which appears to reflect, at least in part, the loss of IP's anti-platelet activity.
IP activation of animal and human
platelets inhibits their
aggregation response and as one consequence of this inhibition of platelet-dependent
blood clotting
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechan ...
. The PGI
2-IP axis along with the production of
nitric oxide, acting together additively and potentially synergistically, are powerful and physiological negative regulators of platelet function and thereby blood clotting in humans. Studies suggest that the PGI
2-IP axis is impaired in patients with a tendency to develop pathological
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 (th ...
such as occurs in obesity, diabetes, and
coronary artery disease.
Cardiovascular system
IP activation stimulates the dilation of arteries and veins in various animal models as well as in humans. It increases the blood flow through, for example, the pulmonary, coronary, retinal and
choroid circulation. Inhaled PGI
2 causes a modest fall in
diastolic and small fall in systolic blood pressure in humans. This action involves IP's ability to relax vascular smooth muscle and is considered to be one of the fundamental functions of IP receptors. Furthermore, IP(-/-) mice on a high salt diet develop significantly higher levels of
hypertension, cardiac fibrosis, and cardiac
hypertrophy than control mice. The vasodilating and, perhaps, platelet-inhibiting effects of IP receptors likely underlie its ability suppress hypertension and protect tissues such as the heart in this model as well as the heart, brain, and gastrointestinal tract in various animal models of
ischemic injury.
Indeed, IP agonists are used to treat patients pathological
vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...
diseases.
The injection of IP activators into the skin of rodents increases local capillary permeability and swelling; IP(-/-) mice fail to show this increased capillary permeability and swelling in response not only to IP activators but also in a model of carrageenan- or
bradykinin
Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor an ...
-induced paw edema. IP antagonists likewise reduce experimentally-induced capillary permeability and swelling in rats. This actions is also considered a physiological function of IP receptors,
but can contribute to the toxicity of IP activators in patients by inducing, for example, life-threatening
pulmonary edema
Pulmonary edema, also known as pulmonary congestion, is excessive liquid accumulation in the tissue and air spaces (usually alveoli) of the lungs. It leads to impaired gas exchange and may cause hypoxemia and respiratory failure. It is due ...
.
IP activators inhibit the adherence of circulating platelets and leukocytes adherence to vascular endothelium thereby blocking their entry into sites of tissue disturbance. The activators also inhibit vascular smooth muscle cells from proliferation by blocking these cells'
growth cycle and triggering their
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
(i.e.
cell death). These actions, along with its anti-inflammatory effects, may underlie the ability of IP gene knockout in an ApoE(−/−) mouse model to cause an accelerated rate of developing atherosclerosis.
Inflammation
Mouse studies indicate that the PGI
2-IP axis activates cellular signaling pathways that tend to suppress allergic inflammation. The axis inhibits bone marrow-derived
dendritic cells (i.e.
antigen-presenting cells that process
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respon ...
material,
present it on their surfaces for delivery to
T cells, and otherwise regulate
innate and
adaptive immune system
The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
responses) from producing pro-inflammatory cytokines (e.g.
IL-12,
TNF-alpha,
IL-1-alpha, and
IL-6) while stimulating them to increase production of the anti-inflammatory cytokine, IL-10. IP receptor activation of these cells also blocks their
lipopolysaccharide
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O- antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the out ...
-stimulated expression of pro-inflammatory cell surface proteins (i.e.
CD86,
CD40, and
MHC class II
MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cell ...
molecules) that are critical for developing adaptive immune responses. IL receptor-activated bone marrow-derived dendritic cells showed a greatly reduced ability to stimulate the proliferation of
T helper cell as well as the ability of these cells to produce pro-allergic cytokines (i.e.
IL-5 and
IL-13)s. In a mouse model of allergic inflammation, PGI
2 reduced the maturation and migration of lung mature dendritic cells to
Mediastinal lymph node Mediastinal lymph nodes are lymph nodes located in the mediastinum.
Pathology
*Mediastinal lymphadenopathy
*Mediastinal mass
A mediastinal tumor is a tumor in the mediastinum, the cavity that separates the lungs from the rest of the chest. It cont ...
s while increasing the egress of immature dendritic cells away from the lung. These effects resulted in a decrease in
allergen
An allergen is a type of antigen that produces an abnormally vigorous immune response in which the immune system fights off a perceived threat that would otherwise be harmless to the body. Such reactions are called allergies.
In technical t ...
-induced responses of the cells mediating allergic reactivity,
TH-2 cells. These IP-induced responses likely contribute to its apparent function in inhibiting certain mouse
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 ...
responses as exemplified by the failure of IP receptor deficient mice to develop full lung airway allergic responses to ovalbumin in a model of allergic inflammation.
In human studies, PGI
2 failed to alter bronchoconstriction responses to allergen but did protect against exercise-induced and ultrasonic water-induced bronchoconstriction in asthmatic patients. It also caused bronchodilation in two asthmatic patients. However, these studies were done before the availability of potent and selective IP agonists. These agonists might produce more effective inhibitor results on airways allergic diseases but their toxicity (e.g. pulmonary edema, hypotension) has tended to restrict there study in asthmatic patients.
IP receptors also appear involved in suppressing non-allergic inflammatory responses. IP receptor-deficient mice exhibit a reduction in the extent and progression of inflammation in a model of collagen-induced arthritis. This effect may result from regulating the expression of arthritis-related, pro-inflammatory genes (i.e. those for
IL-6,
VEGF-A, and
RANKL
Receptor activator of nuclear factor kappa- ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiati ...
).
On the other hand, IP receptors may serve to promote non-allergic inflammatory responses: IP receptor-deficient mice exhibited increased lung inflammation in a model of
bleomycin
-13- (1''H''-imidazol-5-yl)methyl9-hydroxy-5- 1''R'')-1-hydroxyethyl8,10-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazapentadec-1-yl}-2,4'-bi-1,3-thiazol-4-yl)carbonyl]amino}propyl)(dimethyl)sulfonium
, chemical_formula =
, C=55 , H=84 , N=1 ...
-induced
pulmonary fibrosis while mice made to over-express the PGI
2-forming enzyme,
Prostacyclin synthase
Prostaglandin-I synthase () also known as prostaglandin I2 (prostacyclin) synthase (PTGIS) or CYP8A1 is an enzyme involved in prostanoid biosynthesis that in humans is encoded by the ''PTGIS'' gene. This enzyme belongs to the family of cytochrome ...
, in their airway
epithelial cells were protected against lung injury in this model.
Pain perception
IP(-/-) mice exhibit little or no writhing responses in an acetic acid-induced pain model. The mouse IP receptor also appears to be involved in the development of heat-induced
hyperalgesia. These and further studies using IP receptor antagonists in rats indicate that IP receptors on
pain-perceiving sensory neurons of the
dorsal root ganglia as well as on certain neurons in the spinal cord transmit signals for pain, particularly pain triggered by inflammation.
Clinical significance
Toxicity
IP receptor agonists, particularly when used intravenously, have been associated with the rapid development of pulmonary edema, hypotension, bleeding due to inhibition of platelet aggregation, and tachycardia.
Clinical use of these agonists is contraindicated in patients suffering many conditions. For example, the IP agonist
iloprost is contraindicated in patients with unstable
angina; decompensated
cardiac failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
(unless under close medical supervision); severe
cardiac arrhythmias; congenital or acquired
heart valve defects; increased risk of bleeding; a history of
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...
in the past 6 months; or a history of cerebrovascular events (e.g. stroke) within 3 months.
Vasoconstriction
IP receptor agonists are front-line drugs to treat
pulmonary hypertension. Major drugs in this category include PGI
2 itself (i.e.
epoprostenol
Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.
When used as a drug, it is also known as epoprosteno ...
),
iloprost,
treprostinil, and
beraprost with epoprostenol being favored in some studies.
However, newly developed IP agonists with favorable pharmacological features such as
Selexipag
Selexipag, sold under the brand name Uptravi, is a medication developed by Actelion for the treatment of pulmonary arterial hypertension (PAH). Selexipag and its active metabolite, ACT-333679 (or MRE-269, the free carboxylic acid), are agonists ...
have been granted by the
US FDA Orphan Drug status for the treatment of pulmonary hypertension. IP agonists are also to treat severe vasoconstriction in
Raynaud's disease, Raynaud's disease-like syndromes, and
scleroderma.
Epoprostenol causes improvements in hemodynamic parameters and oxygenation in patients suffering the
acute respiratory distress syndrome but due to the limited number of randomized clinical trials and lack of studies investigating mortality, its use cannot be recommended as standard of care for this disease and should be reserved for those refractory to traditional therapies.
A
meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...
of 18 clinical trials on the use of prostanoids including principally IP receptor agonists on patients with severe lower limb peripheral artery disease due to diverse causes found that these drugs may reduce the extent of limb tissue that needed to be amputated. However, the studies did not support extensive use of prostanoids in patients with critical limb ischemia as an adjunct to revascularization or as an alternative to major amputation in cases which cannot undergo revascularization.
Thrombotic diseases
IP receptor agonists have been used to treat
Thromboangiitis obliterans, a disease involving blood clotting and inflammation of the small and medium-sized arteries and veins in the hands and feet.
Genomic studies
An adenine (A) to cytosine (C)
synonymous substitution at base 984 (i.e. A984C) in exon 3 of ''PTGIR is the most frequent
single nucleotide polymorphism (SNP) variant in a sampling of Japanese. This variant was associated with an increase in platelet activation responses in vitro and an increase in incidence of
cerebral ischemia. Two other synonymous SNP variants, V53V and S328S, in ''PTGIR'' in an Italian population study were associated with enhanced platelet activation response and deep vein thrombosis.
The rare SNP variant 795C of 794T in the ''PTGIR'' gene is associated with an increased incidence of
Aspirin-induced asthma
Aspirin exacerbated respiratory disease (AERD), also termed aspirin-induced asthma, is a medical condition initially defined as consisting of three key features: asthma, respiratory symptoms exacerbated by aspirin and other nonsteroidal anti-in ...
and a greater percentage fall in the
forced expiratory volume
Spirometry (meaning ''the measuring of breath'') is the most common of the pulmonary function tests (PFTs). It measures lung function, specifically the amount (volume) and/or speed (flow) of air that can be inhaled and exhaled. Spirometry is he ...
response of airways to inhalation of an aspirin like compound (lysine-acetyl salicylic acid) in a Korean population sample.
See also
* ''PTGIR'' gene (https://www.wikigenes.org/e/gene/e/5739.html)
*
PGI2
*
Prostaglandin receptors Prostaglandin receptors or prostanoid receptors represent a sub-class of cell surface membrane receptors that are regarded as the primary receptors for one or more of the classical, naturally occurring prostanoids viz., prostaglandin D2, (i.e. PGD2) ...
*
Eicosanoid receptor
References
Further reading
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External links
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{{Prostanoidergics
G protein-coupled receptors