Effect of IBMX and alkaline phosphatase inhibitors on Cl- secretion in G551D cystic fibrosis mutant mice.
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 microA/cm2, n = 7; cecum, 3.7 +/- 0.8 microA/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 microA/cm2, n = 6) of a magnitude similar to that seen in wild-type mice (33.7 +/- 4.7 microA/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.
Smith
S N
SN
Ion Transport Unit, National Heart and Lung Institute, London, United Kingdom.
Delaney
S J
SJ
Dorin
J R
JR
Farley
R
R
Geddes
D M
DM
Porteous
D J
DJ
Wainwright
B J
BJ
Alton
E W
EW
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology*; D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors*; D000818:Animals; D002712:Chlorides / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004195:Disease Models, Animal; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D007978:Levamisole / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012007:Rectum / Q000187:drug effects / Q000378:metabolism; D013773:Tetramisole / Q000031:analogs & derivatives / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
D002712:Chlorides; D010726:Phosphodiesterase Inhibitors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D007978:Levamisole; C006226:4-bromotetramisole; D013773:Tetramisole; D000469:Alkaline Phosphatase; D015056:1-Methyl-3-isobutylxanthine