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Disruption of cAMP and Prostaglandin E₂ Transport by Multidrug Resistance Protein 4 Deficiency Alters cAMP-Mediated Signaling and Nociceptive Response

Department of Pharmacology and Developmental Therapeutics Program (Z.P.L., Y.-L.Z., D.R.J., A.C.S.), Section of Comparative Medicine (T.N., J.M.), Cancer Center, and Department of Neurology (B.C.H., S.G.W), Yale University School of Medicine, New Haven, Connecticut, and Department of Chemistry, Colby College, Waterville, Maine (K.P.R.)

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.

Address correspondence to: Alan C. Sartorelli, Department of Pharmacology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520. E-mail: alan.sartorelli{at}yale.edu.