Regulation of prostaglandin EP1 and EP4 receptor signaling by carrier-mediated ligand reuptake

After synthesis and release from cells, prostaglandin E2 (PGE2) undergoes reuptake by the prostaglandin transporter (PGT), followed by cytoplasmic oxidation. Although genetic inactivation of PGT in mice and humans results in distinctive phenotypes, and although experiments in localized environments...

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Main Authors:	Chi, Yuling, Suadicani, Sylvia O, Schuster, Victor L
Format:	Online
Language:	English
Published:	Blackwell Publishing Ltd 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186417/

id	pubmed-4186417
recordtype	oai_dc
spelling	pubmed-41864172014-12-03 Regulation of prostaglandin EP1 and EP4 receptor signaling by carrier-mediated ligand reuptake Chi, Yuling Suadicani, Sylvia O Schuster, Victor L Original Articles After synthesis and release from cells, prostaglandin E2 (PGE2) undergoes reuptake by the prostaglandin transporter (PGT), followed by cytoplasmic oxidation. Although genetic inactivation of PGT in mice and humans results in distinctive phenotypes, and although experiments in localized environments show that manipulating PGT alters downstream cellular events, a direct mechanistic link between PGT activity and PGE2 (EP) receptor activation has not been made. Toward this end, we created two reconstituted systems to examine the effect of PGT expression on PGE2 signaling via two of its receptors (EP1 and EP4). In human embryonic kidney cells engineered to express the EP1 receptor, exogenous PGE2 induced a dose-dependent increase in cytoplasmic Ca2+. When PGT was expressed at the plasma membrane, the PGE2 dose–response curve was right-shifted, consistent with reduction in cell surface PGE2 availability; a potent PGT inhibitor acutely reversed this shift. When bradykinin was used to induce endogenous PGE2 release, PGT expression similarly induced a reduction in Ca2+ responses. In separate experiments using Madin–Darby Canine Kidney cells engineered to express the PGE2 receptor EP4, bradykinin again induced autocrine PGE2 signaling, as judged by an abrupt increase in intracellular cAMP. As in the EP1 experiments, expression of PGT at the plasma membrane caused a reduction in bradykinin-induced cAMP accumulation. Pharmacological concentrations of exogenous PGE2 induced EP4 receptor desensitization, an effect that was mitigated by PGT. Thus, at an autocrine/paracrine level, plasma membrane PGT regulates PGE2 signaling by decreasing ligand availability at cell surface receptors. Blackwell Publishing Ltd 2014-10 2014-07-04 /pmc/articles/PMC4186417/ /pubmed/25505603 http://dx.doi.org/10.1002/prp2.51 Text en © 2014 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Chi, Yuling Suadicani, Sylvia O Schuster, Victor L
spellingShingle	Chi, Yuling Suadicani, Sylvia O Schuster, Victor L Regulation of prostaglandin EP1 and EP4 receptor signaling by carrier-mediated ligand reuptake
author_facet	Chi, Yuling Suadicani, Sylvia O Schuster, Victor L
author_sort	Chi, Yuling
title	Regulation of prostaglandin EP1 and EP4 receptor signaling by carrier-mediated ligand reuptake
title_short	Regulation of prostaglandin EP1 and EP4 receptor signaling by carrier-mediated ligand reuptake
title_full	Regulation of prostaglandin EP1 and EP4 receptor signaling by carrier-mediated ligand reuptake
title_fullStr	Regulation of prostaglandin EP1 and EP4 receptor signaling by carrier-mediated ligand reuptake
title_full_unstemmed	Regulation of prostaglandin EP1 and EP4 receptor signaling by carrier-mediated ligand reuptake
title_sort	regulation of prostaglandin ep1 and ep4 receptor signaling by carrier-mediated ligand reuptake
description	After synthesis and release from cells, prostaglandin E2 (PGE2) undergoes reuptake by the prostaglandin transporter (PGT), followed by cytoplasmic oxidation. Although genetic inactivation of PGT in mice and humans results in distinctive phenotypes, and although experiments in localized environments show that manipulating PGT alters downstream cellular events, a direct mechanistic link between PGT activity and PGE2 (EP) receptor activation has not been made. Toward this end, we created two reconstituted systems to examine the effect of PGT expression on PGE2 signaling via two of its receptors (EP1 and EP4). In human embryonic kidney cells engineered to express the EP1 receptor, exogenous PGE2 induced a dose-dependent increase in cytoplasmic Ca2+. When PGT was expressed at the plasma membrane, the PGE2 dose–response curve was right-shifted, consistent with reduction in cell surface PGE2 availability; a potent PGT inhibitor acutely reversed this shift. When bradykinin was used to induce endogenous PGE2 release, PGT expression similarly induced a reduction in Ca2+ responses. In separate experiments using Madin–Darby Canine Kidney cells engineered to express the PGE2 receptor EP4, bradykinin again induced autocrine PGE2 signaling, as judged by an abrupt increase in intracellular cAMP. As in the EP1 experiments, expression of PGT at the plasma membrane caused a reduction in bradykinin-induced cAMP accumulation. Pharmacological concentrations of exogenous PGE2 induced EP4 receptor desensitization, an effect that was mitigated by PGT. Thus, at an autocrine/paracrine level, plasma membrane PGT regulates PGE2 signaling by decreasing ligand availability at cell surface receptors.
publisher	Blackwell Publishing Ltd
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186417/
_version_	1613141165624786944

Regulation of prostaglandin EP1 and EP4 receptor signaling by carrier-mediated ligand reuptake

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