Prostaglandin E2 EP receptor trafficking and nociception

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Numerous drugs or compounds induce biological functions inside the cells by binding to their own receptors at the cell surface and triggering subsequent intracellular signalling events. In response to the environmental changes, altering the receptor density at the cell surface through its trafficking is a key mechanism to modulate receptor induced cell functions. Prostaglandin E2 (PGE2) is a well known pain mediator abundantly produced in inflamed tissues. PGE2 causes pain through its EP receptors present in pain inducing nerve cells (nociceptors) by directly exciting nociceptors and by stimulating the release of pain causing peptides from these cells. Four EP receptors are located in discrete subcellular domains of nociceptors, with EP1 and EP2 localizing at the cell surface as well as in the intracellular pool while EP3 and EP4 being mainly intracellular. The discrete subcellular distribution of EP receptors is modifiable by pain states, suggesting that PGE2 is able to induce its receptor trafficking to and from the cell surface, thus binding more or fewer PGE2 and consequently enhancing or suppressing pain response. Indeed we also observed that that PGE2 increases the cell surface expression of EP4 receptors in cultured pain inducing nerve cells, which is normally stored in an intracellular pool. Based on these data, we hence hypothesize that PGE2 induces EP4 receptor trafficking to the cell surface of nociceptors to enhance pain response. A research program has been formulated to test this hypothesis. At the initial stage of this research program, we will aim at EP4 trafficking to and from the cell surface at rest and stimulated states, and its role in PGE2 induced pain peptide release. The significance of this research program is to narrow the knowledge gap in our understanding of EP receptor trafficking and its role in modulating PGE2 induced pain. Understanding the mechanisms governing EP receptor trafficking in nociceptors and its role in PGE2 induced pain will potentially open a novel therapeutic avenue to treat various pain conditions in which PGE2/EP receptor signalling is involved.