Prostacyclin receptor

4F8K573919222ENSG00000160013ENSMUSG00000043017P43119P43252NM_000960NM_008967NP_000951NP_032993The 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. 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. 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). 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. Standard prostanoids have the following relative efficacies as receptor ligands in binding to and activating IP: PGI2>>PGD2=PGE2=PGF2α>TXA2. In typical binding studies, PGI2 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, PGI2 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 PGI2 for IP difficult. It also makes it important to have stable synthetic analogs of PGI2 for clinical usage. The most potent of these receptor agonists 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 nanamole/liter range (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=345/). 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/). 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 PGI2 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 and thereby activate cAMP-regulated protein kinases A-dependent cell signaling pathways (see PKA); 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/Ca2+/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 CaCa2 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 FP also stimulates G12/G13-Gβγ G proteins to activate the Rho family of GTPases signaling proteins and Gi-Gβγ G proteins to activateRaf/MEK/mitogen-activated kinase pathways. Studies using animals genetically engineered to lack FP 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. IP gene knockout mice (i.e. IP(-/-) mice) exhibit increased tendency to thrombosis in response to experimentally-induced Endothelium, 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 aggreatation response and as one consequence of this inhibition of platelet-dependent blood clotting. The PGI2-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 2-IP axis is impaired in patients with a tendency to develop pathological thrombosis such as occurs in obesity, diabetes, and coronary artery disease. 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 PGI2 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 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-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.