Eicosanoids And Regulators Proteins


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 Eicosanoids And Regulators Proteins Background

Eicosanoids are a class of lipid mediators that carry information from one cell to another. These cellular messengers have various physiological and pathophysiological roles in fever, inflammation, pain, sleep, gastrointestinal function, bone remodeling, allergic asthma, luteolysis and parturition. The term “eicosa” in Greek means 20 as eicosanoids are derived from polyunsaturated fatty acids containing 20 carbons. They play a vital role in host defense against adverse conditions, e.g. protection against bacterial pathogens. The eicosanoids are part of a family of biologically active lipids derived from the action of cyclooxygenases (COX) or prostaglandin synthases upon the twenty-carbon essential fatty acids or eicosanoids. Prostanoids can be further subdivided into three main groups, the prostaglandins, prostacyclins and thromboxanes. Prostaglandins (PGs) are the major eicosanoids studied in detail beginning with work by Von Euler in 1936, who first reported prostaglandins as vasodilators and muscle stimulating agents derived from the prostate glands of humans and experimental animals. PGs have been used clinically in patients with congenital ductus arteriosus to maintain duct patency until surgical correction. PGs regulate gastric secretion, increase uterine contraction and cause labor induction. Receptors for PGs are a class of 7-trans-membrane domain, G-protein coupled proteins with strong intra-class structural similarities.

Eicosanoids function as local hormones. They are not stored intracellularly, but instead are synthesized “on demand”. Upon cell injury or other stimuli like binding of ligands such as bradykinin or angiotensin II, the rate-limiting enzyme phospholipase A2 translocates to the nuclear envelope, endoplasmic reticulum and Golgi apparatus to release arachidonic acid (AA) from membrane phospholipids. Among the PLA2 isoforms, Type IV cytosolic PLA2 (cPLA2) is the major player involved in eicosanoid synthesis because cells that do not contain this enzyme cannot synthesize eicosanoids. Oxygenation of AA by the rate-limiting enzyme COX (with two isoforms: COX-1 and COX-2) forms intermediate precursors viz., the prostaglandins PGG2 and PGH2 with a half-life of 3 minutes. COX-1 and COX-2 are integral membrane proteins of the endoplasmic reticulum (ER) and nucleus. Subgroups of prostanoid synthases (acting on PGH2) and lipoxygenases (acting on AA directly) produce PGI2, PGE2, PGF2α, PGD2 and TxA2 and leukotrienes (LT). Products of this pathway have a very short half-life (20-30 seconds).

The requirement for two distinct COX enzymes is not fully understood. COX-1, a 70kD protein is found ubiquitously in all tissues and acts as a constitutively active enzyme. The other isoform, COX-2 (72kD), produces prostaglandins in response to inflammatory stimuli. Separate genes encode the two forms of COX but the two forms of COX exhibit structural homology with almost identical catalytic sites. Other differences between COX-1 and COX-2 include varied subcellular localization, substrate specificity and the manner in which they are coupled to upstream and downstream enzymes. In 1994, Picott, Loll and Gravito established the three-dimensional structure of COXs. The small differences in the catalytic domains of these enzymes have been exploited for development of isoform specific inhibitors.

The COX-1 isoform in the endoplasmic reticulum generates PG when there are high levels of AA substrate available to act on. The PG product is then released in an autocrine or paracrine manner to signal downstream through numerous cell-surface G-protein coupled receptors. The main role of the COX-1 products is to maintain homeostasis and hence the name “housekeeping protein.” COX-1 expression in kidney, stomach, vascular endothelium, and blood platelet supports the idea that it is expressed as a signaling mediator in tissues with specialized needs. In platelets the COX-1 product thromboxane is a potent vasoconstrictor and causes platelet aggregation.

COX-2 on the other hand is an inducible enzyme in most tissues. However the kidney and brain COX-2 is constitutively active. Stimuli like cytokines, growth factors and tumor promoters, produced as part of an inflammatory response, lead to eicosanoid synthesis from even low concentrations of the substrate AA in cell types involved in inflammatory responses like macrophages and monocytes. The prostanoids then help resolve the inflammation.

 

Prostaglandin E2

Prostaglandin E is synthesized from the precursor PGH2 by prostaglandin E synthases cytosolic-PGES (c-PGES) and microsomal-PGDS (m-PGES- 1 and m-PGES-2). Cytosolic PGES is constitutively expressed in various tissues, however microsomal PGDS is a perinuclear protein. PGE2 has a very short half-life of 30 seconds. PGE2 acts locally by binding to its receptors EP1, EP2, EP3 or EP4. EP1 is a Gq coupled receptor that increases IP3 by calcium signaling. EP2 and EP4 are Gs coupled receptors that increase cAMP. The EP3 receptor is a Gi coupled receptor that decreases cAMP and increase calcium. PGE2 has proinflammatory effects: for example, LPS-induced PGE2 production causes harmful effects on neurons and enhances pain sensations. On the other hand, PGE2 blocks LPS-induced cytokine synthesis and neuroinflammation providing evidence for an anti-inflammatory effect.

 

Prostaglandin D2

PGD2 is the major prostaglandin synthesized in the brain. Its precursor PGH2 is acted upon by lipocalin type PGD2 (L-PGDS) or hematopoietic PGD2 (h-PGDS). L-PGDS is present in cells of a variety of tissues especially in the central nervous system. H-PGDS is predominant in the cytosol of immune and inflammatory cells. The CP, leptomeninges and oligodendrocytes synthesize L-PGDS in the CNS. It is unique in that it functions not only as a synthase to form PGD2 but also acts as a carrier for lipophilic molecules. L-PGDS is secreted into the cerebrospinal fluid and is also known as beta trace protein. Other sites of PGD2 synthesis are mast cells and leukocytes (dendritic cells and T helper 2 cells). PGD2 is metabolized into PGJ2 and 15d-PGJ2. PGJ2 is then converted into 15-deoxy-∆12, 14-PGJ2 and ∆12-PGJ2. 15-deoxy-∆12, 14-PGJ2 acts as a ligand for the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) and inhibits nuclear factor kappa light chain enhancer of kappa light chain enhancer of B cells (NFKB). A proinflammatory effect of PGD2 is mediated through the Gs-protein coupled DP1 receptor that increases cAMP; and the DP2 receptor, a Gi coupled receptor that decreases cAMP and increases intracellular calcium. PGD2 is involved in type I acute allergic responses, pain perception and regulating physiological sleep.

 

Prostaglandin I2

PGI2 is synthesized by prostacyclin synthase (PGIS) that is co-localized with COX-1 in the endoplasmic reticulum and constitutively expressed by endothelial cells. PGI2 is a potent vasodilator and inhibits platelet aggregation. PGI2 is metabolized by non-enzymatic hydrolysis to form the inactive product 6-keto-PGF1α. PGI2 acts through Gs, Gi or Gq coupled receptors to decrease cAMP and increase IP3 signaling. Relevant IP receptors are localized in kidney, liver, lung, platelets, aorta and heart.

 

Prostaglandin F2α

PGF synthase acts on PGH2 to form PGF2α. It is required for normal parturition and plays an important role in ovulation and contraction of uterine smooth muscle cells. The PGF2α receptor FP is a Gq coupled receptor and its deletion reduces blood pressure and atherosclerosis. 15-keto-dihydro-PGF2α is the main metabolic product of PGF2α and can be detected in the plasma and urine as an indicator of PGF2α produced in response to acute or chronic inflammation.

 

Thromboxane

Thromboxane A2 is synthesized by thromboxane synthase mainly in mast cells and macrophages. Later TxA2 is converted into inactive TxB2. The actions of TxA2 are through the Gq, G12/13 or small G protein coupled receptor TP that increases cAMP, intracellular calcium and IP3 signaling. TxA2 promotes platelet adhesion and smooth muscle contraction. TP receptor deletion has been linked to lower blood pressure response but also bleeding defects.