After being liberated from the cell membrane by phospholipase A2, arachidonic acid is converted to Prostaglandin H2 (PGH2) via the Prostaglandin Endoperoxide H Synthases 1 and 2 (alternate names for the cyclooxygenase enzymes COX1 and COX2) and this process uses O2 to convert arachidonic acid to the unstable peroxide intermediate of PGG2 which then passively reconfigures into PGH2;[34] PGH2 serves as a parent intermediate for all other AA-derived prostaglandins (a subset of eicosanoid).[35] This first stage of eicosanoid synthesis is one of the reason for the antiinflammatory and antiplatelet effects of COX inhibitors (such as aspirin) which prevent AA eicosanoids from being made by reducing PGH2 production.[36][37][38]
In regards to the enzymes that mediate this conversion, COX2 is the inducable form that can be activated in response to inflammatory stressors in as little as 2-6 hours in a variety of cells[39][40][41] although it may be expressed at basal conditions in some cells (brain,[42] testes,[43] and the kidney cells known as macula densa[44]) while COX1 is just generally expressed in all cells;[45] it is due to this variation that COX2 is referred to as the inducible variant and COX1 the constitutive variant.
Arachidonic acid (AA) is liberated from the cell membrane by phospholipase A2, and then is converted into PGH2 (a prostaglandin) via one of the two COX enzymes. Inhibiting this stage inhibits production of all AA-derived eicosanoids, and after PGH2 is synthesized then it can branch out to other eicosanoids
PGH2 can be converted to Prostaglandin D2 via the enzyme prostaglandin D synthase (in the presence of sulfhydryl compounds)[46] and PDG2 is most well known to signal via the DP2 receptor (initially discovered on T cells and named CRTh2[47][48] and also referred to as GRP44[49] and coupled to a Gi or G12 protein[50]). In this sense and via signalling through its receptor, PGD2 is biologically active.
PGD2 can be converted to PGF2α which can bind to its own receptor (PGF2α receptor)[51] as well as the DP2 receptor, albeit 3.5-fold weaker than PGD2.[52] An isomer of PGF2α known as 9α,11β-PGF2 can also be produced from PGD2[53][54] and is equivalent in potency on the DP2 receptor.[53]
PGH2 can be converted to the prostaglandin D2, which is one of the few metabolic 'branches' of prostaglandins. After conversion into PGD2, further metabolism into 9α,11β-PGF2 and PGF2α can occur and these three molecules all possess similar effects
PGH2 (parent prostaglandin) can also be converted into prostaglandin E2 (PGE2) via the enzyme PGE synthase (of which there are a few, the membrane bound ones mPGES-1 and mPGES-2 and the cytosolic one cPGES[55]), and further metabolism of PGE2 results in PGF2. Interestingly, selective inhibition of the inducible enzyme (mPGES-1) appears to attenuate production of PGE2 without affecting concentrations of other prostaglandins downstream of PGH2[56][57][58] while indiscriminately suppressing COX enzymes suppresses all prostaglandins, and inhibiting PGE2 production causes a slight recompensation and increase in PGI2 levels (via COX2).[59][50]
PGE2 tends to be involved in pain as they are expressed in sensory neurons,[55] inflammation,[60] and potentially muscle loss.[61]
There are four receptors for prostaglandin E2 named EP1-4, which are all G-protein coupled receptors. EP1 is coupled to the Gq/11 protein and its activation can increase activity of phospholipase C (producing IP3 and diacylglycerol and thus activating PKC). The EP2 and EP4 receptors are both coupled to the Gs protein and activate adenyl cyclase (creatine cAMP and activating PKA).[62][55][63] EP3 receptors appear to be a tad more complex (being spliced into alpha, beta, and gamma variants; EP3α, EP3β, and EP3γ) but are all coupled to Gi which suppresses the activity of adenyl cyclase (and thus opposes EP2 and EP4) except EP3γ is coupled to both Gi and Gs proteins (inhibiting and activating adenyl cylase).[55][64][65]
The group of enzymes known as PGE synthases, but particularly mPGES-1, converts the parent prostaglandin into PGE2 which serves a role in promoting inflammation and pain perception. PGE2 activates the prostaglandin E receptors (EP1-4)
PGH2 (parent prostaglandin) may be subject to the enzyme prostacyclin synthase and be converted into the metabolite known as prostacyclin or PGI2, which can be further converted into 6-keto-PGF1α (and then converted to the urinary metabolite known as 2,3-dinor-6-keto Prostaglandin F1α). PGI2 is known to activate the I prostanoid receptor (PI)[66][50] which is expressed in the endothelium, kidneys, platelets, and brain.[50]
Prostacyclin production attenuates the pro-platelet function of thromboxanes (next section).[67]
PGH2 can be converted to PGI2, which is also called prostacyclin, and then this prostaglandin signals via the PI receptor
Somewhat unrelated to the prostaglandin class but still derived from the parent prostaglandin, when PGH2 is subject to the enzyme known as thromboxane synthase it is converted into Thromboxane A2. Thromboxane A2 (TxA2) signals through the the T prostanoid receptors (TP) which is a G-protein coupled receptor with two splice variants (TPα and TPβ) coupled to Gq, G12/13
Thromboxane A2 is best known for being produced in activated platelets from when the platelet is stimulated and arachidonic acid is released[67] and its suppression by COX inhibitors (namely aspirin) underlies the antiplatelet effects of COX inhibition.[68]
Thromboxane A2 is a metabolite of the parent prostaglandin (PGH2) that acts upon the T prostanoid receptors, it is most well known to being very pro-platelet formation and exacerbating blood clotting (and inhibition of Thromboxane A2 underlies the antiplatelet benefits of aspirin)
