The activity of PGE
2 is mediated by a group of rhodopsin-type G-protein-coupled membrane receptors (GPCRs) denominated E-prostanoid (EP) receptors [
41]. There are four GPCR subtypes: EP1, EP2, EP3 and EP4. The physiological and contrasting effects of PGE
2 depend on the expression or the co-expression of more than one receptor or isoform [
42]. Additionally, each receptor may be differentially expressed in tissues. EP receptors differ in terms of intracellular signalling [
43],[
44]. These receptors could be classified according to their intracellular signalling and second messenger [
45]. The EP1 receptor signals via Ca
2+ mobilization with slight phosphatidylinositol activity [
46],[
47]. Distribution of this receptor in human tissues and cells is restricted and has been demonstrated in the myometrium, pulmonary veins, mast cells, colonic longitudinal muscle and keratinocytes. EP1 exerts mostly constrictive functions, however and compared with other prostanoid receptors, it seems to be less studied [
47]. EP2 and EP4 receptors increase intracellular cyclic adenosine monophosphate (cAMP) through activation of adenyl cyclase [
39],[
48]. Functional studies have demonstrated that the EP2 receptor is widely distributed [
49] and it seems to be involved in processes of relaxation such as bronchodilation [
50] and anti-inflammation [
51]. On the other hand, EP4 is also widely distributed [
44]. In a direct comparison with EP2 receptor subtype signalling, the EP4 receptor demonstrated a less efficient functional coupling to cAMP [
52],[
53]. Effectively, studies have reported several cAMP-independent signalling pathways for EP4 receptor activation [
54]–[
59]. EP4 mediates vasorelaxation of pulmonary arterial veins and also promotes anti-inflammatory effects [
60]. Consistent with its bronchoprotective action, PGE
2 inhibited proliferation and migration of bronchial smooth muscle cells through the action of the EP4 receptor [
61]. Studies have revealed that the EP3 receptor shows a wide distribution in almost all tissues and consists of multiple isoforms generated by numerous alternative splicing of the C-terminal [
62]–[
64]. Signalling through this receptor reduces the levels of cAMP and increases intracellular Ca
2+[
44]. EP3 exerts mainly contractile functions such as the constriction of human pulmonary artery in the lung [
65]. Moreover, this receptor has been implicated in inflammation, pain and cough [
47],[
66].
In summary, EP2 and EP4 receptor signalling promotes the accumulation of cAMP which is normally related to inhibition of cell functions. On the other hand, EP1 and EP3 receptors that increase intracellular calcium could be associated with cellular activation.