FIGURE 1.

Eicosanoid biosynthesis and PGE2 signaling via EP receptors. (A) Biosynthesis of eicosanoids relies on the release of free arachidonic acid (AA) from membrane phospholipids via phospholipase A2 (PLA-2) or conversion of diacylglycerol to AA through phospholipase C (PLC). An alternative source of AA includes 2-arachidonoylglycerol (2-AG). AA is converted to prostaglandin H2 (PGH2) via the action of COX enzymes, COX-1 and COX-2. PGH2 can be converted to other derivatives, including PGE2 by PGE synthases. (B) PGE2 stimulates at least four different G-protein coupled receptors (EP1, EP2, EP3, and EP4). Stimulation of EP2 and EP4 receptors lead to an increase in intracellular cAMP levels by conversion of ATP to cAMP by adenylate cyclase (AC), while EP3 decreases intracellular cAMP levels by binding to the inhibitory G-protein subunit to AC upon PGE2 stimulation. The EP4 receptor stimulates PI3K pathway independent of cAMP, such as by modulating gene expression via NF-κB. EP1 activity is linked to the mobilization of intracellular Ca²⁺ by activating the phospholipase C pathway.