Prostacyclin receptor

Source: Wikipedia, the free encyclopedia.
(Redirected from
IP receptor
)
PTGIR
Available structures
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000160013

ENSMUSG00000043017

UniProt

P43119

P43252

RefSeq (mRNA)

NM_000960

NM_008967

RefSeq (protein)

NP_000951

NP_032993

Location (UCSC)Chr 19: 46.62 – 46.63 MbChr 7: 16.64 – 16.64 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The Prostacyclin receptor, also termed the prostaglandin I2 receptor or just IP, is a receptor belonging to the prostaglandin (PG) group of receptors. IP binds to and mediates the biological actions of prostacyclin (also termed Prostaglandin I2, PGI2, or when used as a drug, epoprostenol). IP is encoded in humans by the PTGIR gene. 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.

Gene

The PTGIR 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).[5]

Expression

IP is most highly expressed in brain and thymus and is readily detected in most other tissues. It is found throughout the vascular network on endothelium and smooth muscle cells.[5][6]

Ligands

Activating ligands

Standard

Kd values (i.e. concentrations which bind to half of available IP receptors) in the low nanomole/liter range (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=345/).[7]

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 Kd 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.

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.[10]

Platelets

IP

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 PGI2-IP axis is impaired in patients with a tendency to develop pathological thrombosis such as occurs in obesity, diabetes, and coronary artery disease.[10][14]

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

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.[10] Indeed, IP agonists are used to treat patients pathological vasoconstriction diseases.[15] 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-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,[7][10] but can contribute to the toxicity of IP activators in patients by inducing, for example, life-threatening pulmonary edema.[15]

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 (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.[7] [10]

Inflammation

Mouse studies indicate that the PGI2-IP axis activates cellular signaling pathways that tend to suppress allergic inflammation. The axis inhibits bone marrow-derived

CD40, and MHC class II 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, PGI2 reduced the maturation and migration of lung mature dendritic cells to Mediastinal lymph nodes while increasing the egress of immature dendritic cells away from the lung. These effects resulted in a decrease in allergen-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 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.[7][6]

In human studies, PGI2 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.[6]

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

epithelial cells were protected against lung injury in this model.[6]

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

dorsal root ganglia as well as on certain neurons in the spinal cord transmit signals for pain, particularly pain triggered by inflammation.[7][10]

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.

cardiac arrhythmias; congenital or acquired heart valve defects; increased risk of bleeding; a history of myocardial infarction
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

Raynaud's disease, Raynaud's disease-like syndromes, and scleroderma.[20][21] 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.[17] A meta-analysis 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.[22]

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.[23]

Genomic studies

An adenine (A) to cytosine (C)

forced expiratory volume response of airways to inhalation of an aspirin like compound (lysine-acetyl salicylic acid) in a Korean population sample.[25][26]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000160013 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000043017 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "PTGIR prostaglandin I2 receptor [Homo sapiens (Human)] - Gene - NCBI".
  6. ^
    PMID 25541289
    .
  7. ^
    PMID 21508345
    .
  8. ^
    S2CID 207058745
    .
  9. PMID 18946232
    .
  10. ^
    PMID 21752876
    .
  11. S2CID 1513449
    .
  12. PMID 26980701
    .
  13. S2CID 7766467
    .
  14. S2CID 26734051
    .
  15. ^
    PMID 23850788
    .
  16. ^
    S2CID 20499189
    .
  17. ^
    S2CID 19698203
    .
  18. PMID 26825901
    .
  19. PMID 28096285
    .
  20. PMID 25673314
    .
  21. PMID 28018840
    .
  22. PMID 26516035
    .
  23. PMID 32364620
    .
  24. PMID 27708579
    .
  25. S2CID 29436581
    .
  26. PMID 27990118
    .

Further reading

External links

  • "Prostanoid Receptors: IP1". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2008-12-09.
  • Overview of all the structural information available in the PDB for UniProt: P43252 (Mouse Prostacyclin receptor) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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