Spatiotemporal coupling of cAMP transporter to CFTR chloride channel function in the gut epithelia.

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.
Mesh Terms:
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
Cell
Date: Nov. 30, 2007
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