Activation of CFTR by UCCF-029 and genistein.
The mechanism of action of a novel CFTR activator UC(CF)-029 on NIH3T3 cells stably expressing DeltaF508-CFTR was investigated and its effects compared to those of genistein, a known CFTR activator. This study shows that UC(CF)-029 and genistein have differing efficacies. The efficacy of UC(CF)-029 in the presence of forskolin (10microM) is approximately 50% that of genistein; however, the EC(50)'s for both drugs are comparable; 3.5microM for UC(CF)-029 and 4.4muM for genistein. Using NIH3T3 cells stably transfected with K1250A-CFTR we find that CFTR channel open time is unaffected by UC(CF)-029 or genistein, supporting the hypothesis that these compounds stabilize the open state by inhibiting ATP hydrolysis at NBD2. Our data suggest that the ability of UC(CF)-029 to augment DeltaF508-CFTR channel activity necessitates further interest.
Al-Nakkash
Layla
L
Department of Physiology, Midwestern University, 19555 N 59th Avenue, Glendale, AZ 85308, USA. lalnak@midwestern.edu
Springsteel
Mark F
MF
Kurth
Mark J
MJ
Nantz
Michael H
MH
D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000188:drug therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D019833:Genistein / Q000494:pharmacology*; D006868:Hydrolysis; D051379:Mice; D008956:Models, Chemical; D041681:NIH 3T3 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014162:Transfection
C527579:2-pyridin-7,6-benzoflavone; D001571:Benzoflavones; D047428:Protein Kinase Inhibitors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D000255:Adenosine Triphosphate; D019833:Genistein