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Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel localized at apical cell membranes and exists in macromolecular complexes with a variety of signaling and transporter molecules. Here, we report that the multidrug resistance protein 4 (MRP4), a cAMP transporter, functionally and physically associates with CFTR. Adenosine-stimulated CFTR-mediated chloride currents are potentiated by MRP4 inhibition, and this potentiation is directly coupled to attenuated cAMP efflux through the apical cAMP transporter. CFTR single-channel recordings and FRET-based intracellular cAMP dynamics suggest that a compartmentalized coupling of cAMP transporter and CFTR occurs via the PDZ scaffolding protein, PDZK1, forming a macromolecular complex at apical surfaces of gut epithelia. Disrupting this complex abrogates the functional coupling of cAMP transporter activity to CFTR function. Mrp4 knockout mice are more prone to CFTR-mediated secretory diarrhea. Our findings have important implications for disorders such as inflammatory bowel disease and secretory diarrhea.

Original publication

DOI

10.1016/j.cell.2007.09.037

Type

Journal article

Journal

Cell

Publication Date

30/11/2007

Volume

131

Pages

940 - 951

Keywords

Animals, Cell Compartmentation, Cell Membrane, Cells, Cultured, Chloride Channels, Cyclic AMP, Cystic Fibrosis Transmembrane Conductance Regulator, Diarrhea, HT29 Cells, Humans, Intestinal Mucosa, Mice, Mice, Knockout, Models, Biological, Multidrug Resistance-Associated Proteins, Propionates, Protein Binding, Quinolines, Time Factors