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

Journal article

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.

Authors: Li, C; Krishnamurthy, P; Penmatsa, H; Marrs, K; Wang, X

• Journal: Cell
• Volume: 131
• Issue: 5
• Pages: 940-951
• Publication date: 2007-11-01
• DOI: 10.1016/j.cell.2007.09.037
• EISSN: 1097-4172
• ISSN: 0092-8674
• Language: English
• Keywords: Chloride Channels; Multidrug Resistance-Associated Proteins; Animals; Diarrhea; Cyclic AMP; Cells, Cultured; Cystic Fibrosis Transmembrane Conductance Regulator; Mice, Knockout; Protein Binding; HT29 Cells; Time Factors; Cell Membrane; Intestinal Mucosa; Humans; Mice; Quinolines; Models, Biological; Propionates; Cell Compartmentation