Prostaglandin E Receptor Subtype 4 Signaling in the Heart: Role in Ischemia/Reperfusion Injury and Cardiac Hypertrophy

Figure 1

Differential signaling pathway of EP4. In response to PGE₂, activation of EP4 stimulates stimulatory Gα protein (Gsα)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element binding protein (CREB) pathway or Gsα/cAMP/exchange protein directly activated by cAMP (Epac) pathway. EP4 is also coupled to inhibitory Gα protein (Giα), which inhibits the cAMP/PKA/CREB pathway. Furthermore, EP4 activates phosphatidylinositol 3-kinase (PI3K) through activation of Giα. Activation of PI3K not only stimulates the protein kinase B (PKB)/CREB pathway but also induces the expression of early growth response factor 1 (EGR-1) through extracellular signal-regulated kinase signaling. Prostaglandin E receptor 4-associated protein (EPRAP) can inhibit phosphorylation of p105 and further suppress the activation of nuclear factor kappa B (NFκB). AC = adenylyl cyclase; ATP = adenosine triphosphate; GDP = guanosine diphosphate; GTP = guanosine triphosphate.