verlukast and Diarrhea

Topics: Bacterial Toxins; Caco-2 Cells; Cell Line, Tumor; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Diarrhea; Enterotoxigenic Escherichia coli; Enterotoxins; Epithelial Cells; Escherichia coli Infections; Escherichia coli Proteins; Fimbriae Proteins; Humans; Jejunum; Membrane Glycoproteins; Peptide Hydrolases; Propionates; Quinolines; Virulence Factors

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.

Topics: 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