TY - JOUR T1 - Disruption of cAMP and Prostaglandin E<sub>2</sub> Transport by Multidrug Resistance Protein 4 Deficiency Alters cAMP-Mediated Signaling and Nociceptive Response JF - Molecular Pharmacology JO - Mol Pharmacol SP - 243 LP - 251 DO - 10.1124/mol.107.039594 VL - 73 IS - 1 AU - Z. Ping Lin AU - Yong-Lian Zhu AU - Dennis R. Johnson AU - Kevin P. Rice AU - Timothy Nottoli AU - Bryan C. Hains AU - James McGrath AU - Stephen G. Waxman AU - Alan C. Sartorelli Y1 - 2008/01/01 UR - http://molpharm.aspetjournals.org/content/73/1/243.abstract N2 - Multidrug resistance protein 4 (MRP4; ABCC4) is a member of the MRP/ATP-binding cassette family serving as a transmembrane transporter involved in energy-dependent efflux of anticancer/antiviral nucleotide agents and of physiological substrates, including cyclic nucleotides and prostaglandins (PGs). Phenotypic consequences of mrp4 deficiency were investigated using mrp4-knockout mice and derived immortalized mouse embryonic fibroblast (MEF) cells. Mrp4 deficiency caused decreased extracellular and increased intracellular levels of cAMP in MEF cells under normal and forskolin-stimulated conditions. Mrp4 deficiency and RNA interference-mediated mrp4 knockdown led to a pronounced reduction in extracellular PGE2 but with no accumulation of intracellular PGE2 in MEF cells. This result was consistent with attenuated cAMP-dependent protein kinase activity and reduced cyclooxygenase-2 (Cox-2) expression in mrp4-deficient MEF cells, suggesting that PG synthesis is restrained along with a lack of PG transport caused by mrp4 deficiency. Mice lacking mrp4 exhibited no outward phenotypes but had a decrease in plasma PGE metabolites and an increase in inflammatory pain threshold compared with wild-type mice. Collectively, these findings imply that mrp4 mediates the efflux of PGE2 and concomitantly modulates cAMP mediated signaling for balanced PG synthesis in MEF cells. Abrogation of mrp4 affects the regulation of peripheral PG levels and consequently alters inflammatory nociceptive responses in vivo. The American Society for Pharmacology and Experimental Therapeutics ER -