Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection

Abstract

Modulation of a specific prostanoid synthase or receptor provides therapeutic alternatives to nonsteroidal anti-inflammatory drugs (NSAIDs) for treating pathological conditions governed by cyclooxygenase-2 (COX-2 or PTGS2). Among the COX-2 downstream signaling pathways, the prostaglandin E2 (PGE2) receptor EP2 subtype (PTGER2) is emerging as a crucial mediator of many physiological and pathological events. Genetic ablation strategies and recent advances in chemical biology provide tools for a better understanding of EP2 signaling. In the brain, the EP2 receptor modulates some beneficial effects, including neuroprotection, in acute models of excitotoxicity, neuroplasticity, and spatial learning via cAMP-PKA signaling. Conversely, EP2 activation accentuates chronic inflammation mainly through the cAMP-Epac pathway, likely contributing to delayed neurotoxicity. EP2 receptor activation also engages β-arrestin in a G-protein-independent pathway that promotes tumor cell growth and migration. Understanding the conditions under which multiple EP2 signaling pathways are engaged might suggest novel therapeutic strategies to target this key inflammatory prostaglandin receptor.

Figure 1

COX signaling cascade regulates multiple physiological and pathological events. In response to a variety of stimuli, arachiodonic acid (AA), a 20-carbon fatty acid, is freed from membrane phospholipids by phospholipase A2 (PLA₂), and then converted in a dual enzymatic reaction to unstable intermediate prostaglandin H2 (PGH₂) by cyclooxygenase (COX), which has two forms: COX-1 and COX-2. The COX-1 isozyme is constitutively expressed in most mammalian cells to maintain normal homeostasis, while COX-2 is usually undetectable in most normal tissues but strongly induced by excessive neuronal activity, growth factors, or pro-inflammatory stimuli in activated macrophages and other cells at sites of inflammation. Most non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen and naproxen act as nonselective COX inhibitors, whereas the coxibs selectively inhibit the COX-2 isoform. Short-lived PGH₂ is then quickly converted to five prostanoids: PGD₂, PGE₂, PGF_2α, PGI₂ and TXA₂, by tissue-specific prostanoid synthases. Prostanoids exert their functions by activating a suite of G protein coupled receptors (GPCRs). Two GPCRs (DP1 and DP2) are activated by PGD₂, and four by PGE₂ (EP1, EP2, EP3 and EP4), whereas each of the other three prostanoids activates a single receptor (FP, IP, TP). Prostanoids mediate multiple physiological and pathological effects including inflammation, pain, immunoregulation, mitogenesis, plasticity, and cell injury. Only the major pathways are shown.

Figure 2

Signal transduction by prostaglandin receptor EP2. In response to PGE₂, EP2 receptor mediates both G protein-dependent and -independent signaling pathways to conduct multiple beneficial and deleterious actions. We hypothesize that the EP2 receptor mediates cellular survival and neuroplasticity mainly via cAMP/PKA/CREB pathway, but inflammation and neurotoxicity via cAMP/Epac/Rap signaling, and cell proliferation and migration via β-arrestin. Signaling cross-talk occurs among these three EP2 downstream pathways, but only the major pathways and effects are indicated.

Figure 3

Chemical structures of selective small molecule modulators of the EP2 receptor. Agonists: PGE₂, butaprost, CAY10399, ONO-AE1-259, CP-533536 and compound 9; allosteric potentiators: substance identification number (SID) 14735057, SID 24797125, TG3-95-1 (referred to as compound 1 in Ref. [35]), AS-EP-249a (referred to as compound 2 in Ref. [35]), TG3-88 (referred to as compound 3 in Ref. [35]) and TG3-118-1 (referred to as compound 11 in Ref. [35]); and antagonists: TG4-155, TG4-166, TG6-10-1 and PF-04418948. These EP2 ligands are well characterized for their potency and selectivity. Some of them have been evaluated for pharmacokinetics and tested in animal disease models.

Figure 4

The yin and yang of prostaglandin receptor EP2 in the brain. EP2 receptors in neurons are hypothesized to promote cAMP/PKA-dependent neuroprotection. In contrast, glial EP2 activation leads to neurotoxicity and neurodegeneration partly via cAMP/Epac signaling-mediated upregulation of inflammatory mediators including iNOS, COX-2, NOX and pro-inflammatory cytokines. The net effect of EP2 activation is determined by injury types and is spatiotemporally regulated by responding cells and molecules.