Stimulation of cystic fibrosis transmembrane conductance regulator-dependent short-circuit currents across ΔF508 murine intestines

Background & Aims: The cystic fibrosis transmembrane conductance regulator (CFTR) can be activated by pharmacological manipulation of the protein kinase A pathway in cell lines. Our goals were to stimulate wild-type CFTR in murine intestines via isoform-specific phosphodiesterase inhibition or protein kinase A activation and to apply the optimal stimulus to activate chloride secretion from homozygous Delta F508 jejunum, Methods: The response of T84 cells and sections of murine intestine to various inhibitors and activators was examined by Ussing chamber experiments. Results: Maximal chloride secretion can be activated in T84 cells with application of class III phosphodiesterase inhibitors and in wild-type murine intestines with class I or III phosphodiesterase inhibitors or with activators of type II protein kinase A. Chloride secretion can be stimulated from homozygous Delta F508 murine jejunum using a mixture of inhibitors and activators. Conclusions: Delta F508 CFTR can be activated to levels 4% of wild-type when the combination of protein kinase A type II activators and phosphodiesterase class I and III inhibitors are used in murine jejunum, This result suggests that partial CFTR-mediated electrolyte transport can be restored in Delta F508 murine jejunum by application of specific pharmacological agents.