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Am J Physiol Cell Physiol 274: C492-C499, 1998;
0363-6143/98 $5.00
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Vol. 274, Issue 2, C492-C499, February 1998

Effect of IBMX and alkaline phosphatase inhibitors on Clminus secretion in G551D cystic fibrosis mutant mice

Stephen N. Smith1, Stephen J. Delaney2, Julia R. Dorin3, Raymond Farley1, Duncan M. Geddes1, David J. Porteous3, Brandon J. Wainwright2, and Eric W. F. W. Alton1

1 Ion Transport Unit, National Heart and Lung Institute, London SW3 6LR, United Kingdom; 2 Department for Molecular and Cellular Biology, University of Queensland, Brisbane 4072, Australia; and 3 Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, United Kingdom

Some cystic fibrosis transmembrane conductance regulator (CFTR) mutations, such as G551D, result in a correctly localized Cl- channel at the cell apical membrane, albeit with markedly reduced function. Patch-clamp studies have indicated that both phosphatase inhibitors and 3-isobutyl-1-methylxanthine (IBMX) can induce Cl- secretion through the G551D mutant protein. We have now assessed whether these agents can induce Cl- secretion in cftrG551D mutant mice. No induction of Cl- secretion was seen with the alkaline phosphatase inhibitors bromotetramisole or levamisole in either the respiratory or intestinal tracts of wild-type or cftrG551D mice. In contrast, in G551D intestinal tissues, IBMX was able to produce a small CFTR-related secretory response [means ± SE: jejunum, 1.8 ± 0.9 µA/cm2, n = 7; cecum, 3.7 ± 0.8 µA/cm2, n = 7; rectum (in vivo), 1.9 ± 0.9 mV, n = 5]. This was approximately one order of magnitude less than the wild-type response to this agent and, in the cecum, was significantly greater than that seen in null mice (cftrUNC). In the trachea, IBMX produced a transient Cl- secretory response (37.3 ± 14.7 µA/cm2, n = 6) of a magnitude similar to that seen in wild-type mice (33.7 ± 4.7 µA/cm2, n = 9). This response was also present in null mice and therefore is likely to be independent of CFTR. No effect of IBMX on Cl- secretion was seen in the nasal epithelium of cftrG551D mice. We conclude that IBMX is able to induce detectable levels of CFTR-related Cl- secretion in the intestinal tract but not the respiratory tract through the G551D mutant protein.

mouse model; 3-isobutyl-1-methylxanthine; cystic fibrosis transmembrane conductance regulator


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