EP2, EP4, IP, and DP1 receptors activate adenylyl cyclase via Gs. This leads to increased intracellular cAMP levels, which in turn activate specific protein kinases (see Chapter 2). EP1, FP, and TP activate phosphatidylinositol metabolism, leading to the formation of inositol trisphosphate, with subsequent mobilization of Ca2+ stores and an increase of free intracellular Ca2+. TP also couples to multiple G proteins, including G12/13 and G16, to stimulate small G protein signaling pathways, and may activate or inhibit adenylyl cyclase via Gs (TPα) or Gi (TPβ), respectively. EP3 isoforms can couple to both increased intracellular calcium and to increased or decreased cAMP. The DP2 receptor (also known as the chemoattractant receptor-homologous molecule expressed on Th2 cells, or CRTh2), which is unrelated to the other prostanoid receptors, is a member of the fMLP receptor superfamily. This receptor couples through a Gi-type G protein and leads to inhibition of cAMP synthesis and increases in intracellular Ca2+ in a variety of cell types.
LTB4 also causes inositol trisphosphate release via the BLT1 receptor, causing activation, degranulation, and superoxide anion generation in leukocytes. The BLT2 receptor, a low-affinity receptor for LTB4, is also bound with reasonable affinity by 12(S)and 12(R)-HETE, although the biologic relevance of this observation is not clear. CysLT1 and cysLT2 couple to Gq, leading to increased intracellular Ca2+. Studies have also placed Gi downstream of cysLT2. An orphan receptor, GPR17, binds cysLTs and may negatively regulate the function of cysLT1, but its physiologic role remains ill defined. As noted above, the EETs promote vasodilation via paracrine activation of calcium-activated potassium channels on smooth muscle cells leading to hyperpolarization and relaxation. This occurs in a manner consistent with activation of a Gs-coupled receptor, although a specific EET receptor has yet to be identified. EETs may also act in an autocrine manner directly activating endothelial transient receptor potential channels to cause endothelial hyperpolarization, which is then transferred to the smooth muscle cells by gap junctions or potassium ions. Specific receptors for isoprostanes have not been identified, and the biologic importance of their capacity to act as incidental ligands at prostaglandin receptors remains to be established.
CHAPTER 18 The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds 327
FIGURE 18–4 Prostanoid receptors and their signaling pathways. fMLP, formylated MetLeuPhe, a small peptide receptor; PLC-β, phospholipase C-β. All of the receptors shown are of the seven-transmembrane, G protein-coupled type. The terms “relaxant,”“contractile,” and “inhibitory” refer to the phylogenetic characterization of their primary effects. ** , all EP3 isoforms couple through Gi but some can also activate Gs or G12/13 pathways. RhoGEF, rho guanine nucleotide exchange factor. See text for additional details.
Although prostanoids can activate peroxisome proliferatoractivated receptors (PPARs) if added in sufficient concentration in vitro, it remains questionable whether these compounds ever attain concentrations sufficient to function as endogenous nuclear-receptor ligands in vivo.
Effects of Prostaglandins & Thromboxanes