MolPharm xPharm- The Comprehensive Pharmacology Reference

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on October 24, 2007; DOI: 10.1124/mol.107.039594

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.107.039594v1
73/1/243    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lin, Z. P.
Right arrow Articles by Sartorelli, A. C
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lin, Z. P.
Right arrow Articles by Sartorelli, A. C


Received for publication July 10, 2007.
Revised October 19, 2007.
Accepted for publication October 22, 2007.

Disruption of cAMP and PGE2 Transport by Mrp4 Deficiency Alters cAMP-mediated Signaling and Nociceptive Response

Z. Ping Lin 1, Yong-Lian Zhu 1, Dennis R Johnson 1, Kevin P Rice 2, Timothy Nottoli 1, Bryan C Hains 1, James McGrath 1, Stephen G Waxman 1, Alan C Sartorelli 1*

1 Yale University School of Medicine 2 Colby College

* Address correspondence to: E-mail: alan.sartorelli{at}yale.edu

Abstract

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 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 to 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 impacts the regulation of peripheral PG levels and consequently alters inflammatory nociceptive responses in vivo.


Key words: Phosphodiesterases, Protein Kinase A, Nucleoside/Nucleotide, Organic anion, Regulation of gene expression, Cyclooxygenases, Antiviral drugs, Knockout, RNA/siRNA


This article has been cited by other articles:


Home page
 Cancer Prevention ResearchHome page
S. D. Markowitz
Colorectal Neoplasia Goes with the Flow: Prostaglandin Transport and Termination
Cancer Prevention Research, July 1, 2008; 1(2): 77 - 79.
[Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2007 by the American Society for Pharmacology and Experimental Therapeutics